YOGA VS PILATES. WHICH PRACTICE IS RIGHT FOR YOU?

Eating And Lifestyle For Better Hormone Health In Peri-Menopause

While women’s hormone health is always foundational to overall wellness, a time called perimenopause—the years before menopause, when the ovaries begin to make less oestrogen—is characterized by significant hormonal shifts, in addition to negative symptoms including anxiety, depression, night sweats, and more. .By consuming larger amounts of cruciferous vegetables, which “promote estrogen metabolism and detoxification in the liver,” the article mentions incorporating flaxseed into routines, focusing on foods that support bone health, eating plenty of omega-3-rich foods, and replacing simple & processed sugars with more high-fiber complex carbohydrates. Overall, the research supports a strong focus on foods that “decrease inflammation, support a healthy mood, and balance hormones and insulin levels.”

Here at Compounding Lab , we’re all about women’s hormone health. We strongly believe that our hormones benefit from a healthy lifestyle and that every green smoothie, yoga , pilates class, and minute of meditation matters. But there’s a time in every woman’s hormonal life—called perimenopause—that’s long been overlooked. This era is marked by big hormonal shifts that can greatly affect quality of life, causing a lot of anxiety and discomfort. So this week, lets get down and dirty and uncover our hormones so that we’re all more informed and empowered.

So perimenopause refers to the years that precede menopause, when women can experience unwelcome symptoms of hormones changing like night sweats, mood swings, irritability, depression, missed or heavy periods, and vaginal dryness. These symptoms are no walk in the park! Most women start experiencing perimenopause n their mid-40s, but for some women it will begin as early as their 30s.

So what’s happening to your hormones during this time? During perimenopause, oestrogen and progesterone hormones start to decrease. Progesterone tends to drop first, and oestrogen can fluctuate up and down until it settles. You can’t avoid these hormonal changes altogether, but you can do a lot to empower yourself with specific dietary and lifestyle choices that help you feel more like yourself. Here are some important foods I tell women to focus on during this time in your life:

1. Load Up On Cuciferous Vegetables.

In the early stages of perimenopause, progesterone drops faster than oestrogen. This can lead to oestrogen dominance, or a higher oestrogen level compared to progesterone. During this phase, it’s important to support the body’s ability to metabolize oestrogen properly, and vegetables from the cruciferous family are best at that. “Rich in indole 3-carbinol and chlorophyll, these veggies promote oestrogen metabolism and detoxification in the liver, shifting ‘dirty’ oestrogens to ‘clean’ oestrogens,” I recommend eating cruciferous vegetables on a daily basis during perimenopause. If you’re not used to consuming this type of vegetable and need some inspiration, try sautéing and incorporating broccoli, Brussels sprouts, and bok choy into omelets and stir-fries. You can also mix raw shredded broccoli, cabbage, or Brussels sprouts into your salads. One of my favorite substitutes is to make cauliflower rice instead of mashed potatoes or white rice for more fiber and fewer carbs. Or, simply snack on cruciferous veggies alone or dipped in guacamole or hummus. If they cause gas or bloating, start slowly and stick with cooked forms, as cooking these cruciferous veggies makes them easier for your digestive system to tolerate. If you can’t tolerate them FIX your GUT girls.

2. Eat Protein-Rich Foods At Every Single Meal , Especially Breakfast At Around 10am

Blood sugar issues during perimenopause will worsen your mood swings, increase irritability, and stress your adrenals. Eating protein at every meal will stabilize blood sugar and reduce the spikes and crashes, which will also help you lose weight, prevent weight gain, and reduce your risk for insulin resistance, diabetes, and metabolic syndrome. Protein also helps you stay full and burn more calories without feeling deprived or constantly hungry. Your muscle mass and bone density take a hit as you enter menopause, and getting enough protein in your day, along with resistance training or weights will preserve them and reduce their decline. The best high-protein foods to incorporate into your diet are pastured eggs, wild-caught fish, lean poultry, grass-fed meats, and legumes (if you can tolerate them). Aim for 21 to 28 grams of protein at each meal, including breakfast. Skip the morning pastry and have a savory breakfast like a vegetable omelet or organic, preservative-free turkey or chicken sausage with some broccoli or cauliflower. If you like oatmeal, add high-protein nuts and seeds like almond butter, hemp, or pumpkin seeds for a delicious and high-protein treat.

3. Incorporate Flaxseed Into Your Routine.

Flaxseed can be one of the most supportive superfoods throughout perimenopause. Carper frequently recommends it in the later perimenopause stages as it contains lignans, which are phytoestrogens, weaker plant-based oestrogens that provide gentle oestrogen support when estrogen is waning. Conversely, she adds, “it can act adaptively and block oestrogen when oestrogen dominance is present in the earlier stages.” That said, if adding flaxseed worsens your periods, mood swings, breast tenderness, or other symptoms you’re experiencing, it may be amplifying your oestrogen dominance, and you should discontinue use. Expert tip: Always grind flaxseeds to reap the benefits, as we don’t have the digestive enzymes needed to break down the outer shell. If possible, buy them whole, grind them in small batches every few days, and store in the fridge to maximize freshness. Flaxseeds can be enjoyed in smoothies, as an egg replacement in vegan or egg-free recipes, or simply added to casseroles or Greek yogurt. If you’re into healthy baked goods, you can also use ground flaxseed to replace white or processed flours in muffins and other baked goods to increase fiber and protein.

4. Focus On Foods That Support Bone Health.

OEstrogen protects against bone loss, so when it starts to drop, women are at an increased risk for osteoporosis. This means that perimenopause is a very important time to support your bone health to prevent osteoporosis and its complications. You can do this in a few ways, but this first is by eating calcium-rich foods. If you choose and tolerate dairy, eat two servings per day and choose organic or grass-fed varieties. Plain or Greek yogurt are great options as they also contain live bacteria that support the gut. Skip sweetened and fruit-flavored yogurts and mix in chopped cucumber and fresh herbs instead of fruit as a savory snack. Plain cottage cheese and aged cheeses without additives or colorings are good sources of calcium and protein as well. If you don’t tolerate dairy, there are many nondairy calcium-rich foods to choose from. Try broccoli, bok choy, collard greens, kale, almonds, and canned salmon and sardines with bones. Many of these foods contain vitamin D, which helps your body absorb the calcium, but I find that most of my patients are who are defiecnet in Vit D need to supplement for optimal bone health—especially during perimenopause. To continue to support your bone health during perimenopause, ask your doctor to test your vitamin D levels and take a dose that’s right for you. Aim for 120 level. Two other often overlooked nutrients critical for bone health are magnesium and vitamin K2. Magnesium, found in nuts, legumes, leafy greens, and dark chocolate, is another mineral that makes up your bones. Vitamin K2, found in natto (fermented soy), egg yolks, cheese, and butter, tells your body to deposit the calcium in your bones, not your arteries or other organs. Just like vitamin D, food doesn’t typically provide an adequate amount of vitamin K2. Because of the emerging research on its role in bone health—as well as heart disease and diabetes—I recommend that women during and after perimenopause add a high-quality vitamin K2 supplement to their daily routine.

5. Don’t Forget Omega-3-Rich Foods.

During the transition to menopause, try to eat 4 ounces of omega-3-rich fish like salmon, sardines, tuna, mackerel, cod, and trout twice a week. Research shows that EPA and DHA, the two omega-3 fatty acids found in fish, reduce inflammation, improve mood, and reduce depression. They also reduce the risk for heart disease, another condition that women become at higher risk for after perimenopause. But what about plant-based omega-3s like walnuts and flaxseed? These foods contain the plant-based omega-3 ALA, which needs to be converted to EPA and DHA in order for you to receive the benefits. This means that nut-based omega-3s don’t replace fish-based ones, but they are still a great source of healthy fats and fiber. If you’re at an increased risk of heart disease or don’t like eating fish, ask your doctor about starting a high-quality fish oil supplement.

6. Eat More High-Fiber Complex Carbohydrates (Because Not All Carbs Are Bad).

Cutting out simple and processed sugars and replacing them with high-fiber complex carbohydrates will help balance your blood sugar during perimenopause. Healthy carbohydrates can also reduce mood swings, irritability, and depression and HOT Flushes. They increase the production of serotonin, one of the happy, feed-good hormones. I find that the best types and amounts of carbohydrates will vary from one person to another, as several things must be factored in like your medical history, activity level, and digestive health. If tolerated, beans, lentils, oats, quinoa, buckwheat, and other whole grains a few times a week are good options. Starchy vegetables like sweet potatoes, pumpkin , carrots, beets, winter squashes, and other root vegetables are great choices because they are rich in nutrients and fiber. By focusing on these foods—which can help decrease inflammation, support a healthy mood, and balance hormones and insulin levels—perimenopause doesn’t have to be something we dread. In fact, entering perimenopause is a great excuse to prioritize cooking at home, learning to love healthy foods and exercise, and generally taking a little extra care of yourself. That doesn’t sound like anything we should be afraid of!

cleannutritionals.com.au

Age-Related Cognitive Decline

Lets talk about an issue that all of us have to face after a certain point in our lives: COGNITIVE DECLINE.

 As we grow and develop from children to young adults, there is a palpable upward trend in our mental development and ability, and there is a sense that we are always growing to some greater height. Unfortunately, this trend can’t go on forever, and it is all too clear as the decades progress, that our minds are never going to be quite what they were. 

SOME OF THE QUESTIONS WE FACE:

  • What is the process behind this gradual cognitive decline? 
  • What are the factors involved? Are there any in our control? 
  • Can we slow or stop this process in order to preserve our quality of life? 

Let’s break it down.

WHAT IS COGNITIVE DECLINE?

Cognitive decline is something that is generally known to happen as people age, but there are degrees of decline that can be considered excessive and unhealthy. 
There is no universally accepted definition of successful cognitive health in elderly individuals, but cognitive health is generally defined as “the development and preservation of the multidimensional cognitive structure that enables ongoing social connectedness, sense of purpose, and the ability to function independently” (1). That, broadly speaking, is the definition of the standard of cognitive ability that we all should be able to enjoy for our entire lives. 
Cognition encompasses a broad range of mental processes, which are often taken for granted until they are lost. There are two essential forms of cognition: 

  1. There is “fluid” cognition, which relies on short-term memory to process information when solving new problems, using spatial reasoning and when identifying patterns.
  2. There is also “crystallized” cognition, where knowledge and life experience accumulate, and this relies more on long-term memory (2)

Fluid cognitive abilities are thought to peak in the mid-twenties, and then very gradually decline over a period of years until about age 60, when the decline tends to become more rapid. But this is only for fluid cognition, while crystallized cognition continues to increase over the life span through education and life experiences.

Pathological cognitive decline is something that tends to be seen earlier than expected, or it hits the individual harder than expected, resulting in disruption of social connectedness, and individual autonomy. 

Mild Cognitive Impairment (MCI) is a condition presenting with memory deficits that are below what is considered normal. This condition can often foreshadow the onset of frank dementia, and early detection is very important, so that preventative measures may be taken to stem the progression of the condition.

Signs & Symptoms of MCI (Mild Cognitive Impairment)

Symptoms are often vague and can include the following:

  • Memory loss
  • Language disturbance (eg, difficulty in finding words)
  • Attention deficit (eg, difficulty in following or focusing on conversations)
  • Deterioration in visual-spatial skills (eg, disorientation in familiar surroundings in the absence of motor and sensory conditions that would account for the complaint) 

Cerebrovascular Conditions
Cerebrovascular disease (CVD) is defined as brain lesions caused by vascular disorders. This can be something as dramatic and severe as a stroke, where there is cessation of blood flow to a particular part of the brain, usually caused by a blood clot. But then there is also vascular dementia. 
Vascular dementia is a chronic progressive loss of cognitive function, due to multiple small infarcts (4). These can be thought of as very small mini-strokes that only affect minor sections of brain tissue at a time. By themselves, each one of these little infarcts doesn’t have a huge impact on cognitive function, as the brain is able to re-route to other neural pathways that bypass the section affected by the mini-stroke. 
However, over a period of years, as these mini-strokes accumulate, the available pathways the brain is left with become ever more restrictive, and so because of this you see a progressive decline in cognitive function.  

Prevalence of Dementia
In 2005, the global population suffering dementia was estimated to be 24.3 million people, and there are around 4.6 million new cases diagnosed every year (3). It is expected that this population will double every 20 years, with an alarming 81.1 million dementia patients in 2040 (3). A major consequence of this is an increased burden on the healthcare system, with higher rates of hospitalizations, surgeries and visits to the doctor, leading to spiraling healthcare costs.

DEMENTIA and CHRONIC INFLAMMATION

Chronic systemic inflammation is the underlying culprit of many such chronic conditions, including heart disease, diabetes, cancer, and this very form of progressive damage to the brain. 

Increased chronic inflammation means greater chances of clotting factors activating, and causing the aforementioned “mini-strokes” that promote cognitive decline. Therefore, eating an anti-inflammatory Mediterranean type diet, avoiding simple sugar and carbs, avoiding fried foods and ensuring adequate intake of Omega 3 fatty acids, are some of the basic means of helping to preserve cognitive function as we mature.

In other words, less chronic inflammation, less clotting factors floating around in the system, less potential for oxidative damage, all equals less chance of a mini-clot causing these kinds of tiny infarcts in the brain.

There is a growing body of research demonstrating that adherence to a Mediterranean type diet significantly reduces risk of developing Mild Cognitive Decline, and risk of progression to Alzheimer’s Disease. (5)

MEDITERRANEAN DIET
In general, the Mediterranean diet, which is low calories and rich in fruits and vegetables, has the greatest benefit for reducing inflammation. Data show that high dietary fiber, which is typically a sign of a low glycemic load diet, was associated with lower levels of various inflammatory markers (6).
The dietary pattern most consistently associated with a reduction of CVD is predominantly plant-based, emphasizing fruits, vegetables, whole grains, nuts, fiber, and sources of Omega 3 fatty acids.

EXERCISE!

Cognitive Exercise
Another way to keep the brain functioning well, is just to make sure you are using it well. The brain tissue is very plastic, meaning that it always hast the ability to form new connections, and keep existing connections strong, as long as you challenge it with tasks to do. 
Evidence is not conclusive, but it is generally believed that exercising the brain by reading, doing crossword puzzles, and brain teasers can help to prevent, delay, or reduce cognitive decline. These should always be fun, stimulating activities that you enjoy doing, so that you will want to do them a lot.

Moderate Physical Exercise
Not only is moderate exercise a well established, and yet all too often overlooked, means of reducing chronic inflammation in the body (7), there is a growing body of evidence indicating that it can help prevent mild cognitive impairment as we age. 

SPECIFIC NUTRIENTS
Vitamin D
has been shown to be deficient or insufficient on pandemic levels, and lower levels are associated with several chronic diseases. It serves as a significant factor in a number of physiologic functions, specifically as a biological inhibitor of inflammatory hyperactivity (8, 9, 10). Vitamin D produces dose dependant reductions of several inflammatory markers, and supplemental benefit has been shown for osteoarthritis, multiple sclerosis, type 1 diabetes, Graves Disease, ankylosing spondylitis, SLE, and rheumatoid arthritis (8, 9, 10).
Data from the National Health and Nutrition Examination Survey (NHANES) from 2001-2004, involving more than 8000 human subjects, showed that those with vitamin D levels below 30 ng/ml were more likely to be at high risk of cardiovascular disease.

Fish Oil
A good quality fish oil supplement will be standardized to have large quantities of EPA and DHA, in a 3:1 or 3:2 ratio for adults. These omega 3 fatty acids promote the formation of anti-inflammatory eicosenoids that become incorporated into our cell membranes, helping them to remain fluid and pliable (11). This can help prevent heart disease and any associated cerebrovascular disease in the brain. 

Natural Antioxidants and Anti-inflammatories
Although a diet rich in fruits and vegetables is generally anti-inflammatory, some foods seem to exert some specific benefit along these lines. These include Blueberries (Vaccinium myrtillus), chocolate (dark), cranberries (Vaccinium macrocarpon), garlic (Alliu sativum), ginger (Zingiber officinalis), grape (Vitis vinifera), green tea (Camellia sinsensis), and turmeric (Curcuma longa).

Oxytocin Intranasal Treatment for socialization, obesity, pain, and substance abuse

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Oxytocin is a hormone secreted by the posterior lobe of the pituitary gland, a pea-sized structure at the base of the brain. Sometimes known as the “cuddle hormone” or the “love hormone,” oxytocin promotes feelings of devotion, trust, and bonding and is released through physical touches, such as hugs, and also linked to the intensity of orgasms during sexual activity.

2013 review noted all of oxytocin’s possible relationship-enhancing effects, which were said to include:

  • Fostering pro-relationship mindsets and behaviors
  • Enhancing the processing of bonding cues
  • Facilitating improved communication
  • Empathy
  • Trust
  • Fidelity

For females, it is the neuropeptide responsible for inducing labor contractions in pregnant women and also the “let down reflex,” which stimulates the production of milk during breastfeeding. Oxytocin is synthesized in the hypothalamus and stored in the posterior pituitary where it can be released when needed.

Chapter 16 Nutritional Aspects of Pregnancy and Breastfeeding Vicky Pehling

 Figure 1: Chapter 16- Nutritional Aspects of Pregnancy and Breastfeeding. Vicky Pehling

  1. suckling stimulates nerves in the nipple and areola that travel to the hypothalamus
  2. In response, the hypothalamus stimulates the posterior pituitary to release oxytocin and anterior pituitary to release prolactin
  3. Oxytocin stimulates lobules in the breast to let down (release) milk from storage. Prolactin stimulates additional milk production

Oxytocin Uses In Childbirth

In general, oxytocin should not be used to start labor unless there are specific medical reasons. However, the FDA approves the use of oxytocin for pregnant women who have complications of childbirth, such as:

  • Cardiovascular-Renal Disease
  • Eclampsia
  • Preeclampsia
  • Premature Rupture of Membranes (PROM)

It can also be used to reduce and control postpartum uterine bleeding with minimal side effects, namely nausea, vomiting, and headaches.  

Alternative Uses of Oxytocin

In recent years, it has been suggested that oxytocin may prove beneficial for a number of clinical conditions beyond those approved by the FDA.

Oxytocin uses studied outside of FDA indication include: 

Chronic / Acute Pain – Numerous randomized studies have shown promising results of oxytocin use for chronic and acute pain. 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.(1)

Oxytocin can also modulate pain by counteracting with psychological features such as calming the emotion of pain or removing the cognitive attention to pain.

Autism Spectrum Disorder (ASD) – Oxytocin has been implicated in the regulation of repetitive and affiliative behaviors and stress reactivity. Therefore, it is expected to be a potential therapeutic resource for the social core symptoms of ASD, since this neuropeptide can modulate human social behavior and cognition. (2)

Hypoactive Sexual Desire Disorder (HSDD) – HSDD is attributed to an imbalance in central sexual excitatory (dopamine, norepinephrine, melanocortin, and oxytocin) and sexual inhibitory (serotonin, opioid, endocannabinoid, and prolactin) pathways. For some, treatment with oxytocin nasal spray has shown to improve the sexual quality of life significantly.

Post-Traumatic Stress Disorder (PTSD) – Research findings indicate that repeated intranasal oxytocin offers promising early preventive intervention for PTSD for individuals at increased risk for PTSD due to high acute symptom severity.(3)

Obesity / Weight Loss – Scientists suspect that one element of the obesity epidemic is that the brains of obese people respond differently to images of delicious, calorically dense foods. Studies have shown that oxytocin reduces activation in the hypothalamus, an area of the brain that controls hunger, and increases activation in areas of the brain associated with impulse control. Thus, some believe that the hormone creates less of a need to eat, reduces the compulsion to eat for fun, and improves impulse control when it comes to actually reaching for that second slice of cake.(4

Addiction & Withdrawal – Oxytocin has also been used as a potential mediator and regulator of drug addiction. Several studies have shown good outcomes in cocaine, opioid, and cannabis addiction. In a placebo-controlled trial the administration of oxytocin demonstrated efficacy in reducing withdrawal symptoms, anxiety and need for lorazepam in subjects with alcohol dependence undergoing detoxification.(5)

The ‘Cuddle Hormone’ Might Help America Take On the Obesity Epidemic

A man and a woman cuddle on a rock.

Scientists suspect that one element of the obesity epidemic is that the brains of obese people respond differently to images of delicious, calorically dense foods. Obese individuals’ brains seem to light up at the sight of donuts, pizza, and other calorie bombs, even when they’re no longer hungry.

Some studies have suggested that this heightened activity might predispose people to overeating. Today, nearly 40 percent of American adults are obese, and obesity is predicted to become the leading cause of cancer among Americans, replacing smoking, within five or 10 years. (It’s still not clear yet which comes first—the obesity or the overactive brain activity.) “Part of the reason for the obesity epidemic is that people eat when they’re not hungry,” says Elizabeth Lawson, an associate professor of medicine at Harvard Medical School and a neuroendocrinologist at Massachusetts General Hospital.

A remedy for this over-activation in the brain might come from an unexpected source: oxytocin, the brain chemical often associated with love and social relationships. Oxytocin is sometimes called the “cuddle hormone” because it’s released during sex, childbirth, and breastfeeding. People who are in the early stages of falling in love have higher levels of oxytocin than normal. The drug ecstasy also increases concentrations of the hormone in the blood.

Oxytocin has a variety of other surprising functions. A form of the chemical, Pitocin, induces labor, and another form might help treat stomach pain. Early studies have suggested that the hormone might boost social skills among kids with autism. Now Lawson and other researchers are investigating whether oxytocin might also prevent overeating.

Lawson and her colleagues recently showed images of high-calorie foods to 10 overweight and obese men. She found that the regions of the brain involved in eating for pleasure lit up when the men viewed the images. A dose of oxytocin, compared with a placebo, weakened the activity in those regions, and it also reduced the activity between them. Meanwhile, oxytocin didn’t have that effect when the men viewed images of low-calorie foods or household items. Lawson’s colleagues presented the research, which has not yet been published in a peer-reviewed journal, last month at Endo 2019, the Endocrine Society’s annual meeting.

“One of the key ways oxytocin works in limiting the amount of food that we eat is that it speeds up the satiety process, or reaching fullness,” says Pawel Olszewski, an associate professor of physiology at the University of Waikato, in New Zealand, who was not involved with Lawson’s study. “Then, oxytocin works through brain areas that are associated with the pleasure of eating, and it decreases our eating for pleasure.

That’s just one of the ways oxytocin shows potential as an obesity treatment. Previously, Lawson and her colleagues found that the hormone improves insulin sensitivity and encourages the body to use fat as fuel. Lawson’s other studies have shown that oxytocin reduces activation in the hypothalamus, an area of the brain that controls hunger, and increases activation in areas of the brain associated with impulse control. To Lawson, the results together suggest that the hormone creates less of a need to eat, reduces the compulsion to eat for fun, and improves impulse control when it comes to actually reaching for that second slice of cake. Oxytocin, in other words, appears to make food seem less rewarding.

Other researchers have found that oxytocin might weaken alcoholics’ dependence on alcohol, drawing parallels to the hormone’s effects on how some obese people’s brains perceive food. A study published in the journal PLOS this month showed that oxytocin cut the desire to drink among alcohol-dependent rats. It’s not clear what this anti-drinking element of oxytocin has to do with its love-hormone properties, if anything.

So why can’t we just pick up bottles of oxytocin at CVS? For one thing, most of these studies have been very small; 10 is a minuscule sample size. They’ve been largely conducted on men, so future research would need to be expanded to women. The mechanism behind oxytocin’s effects on eating behavior and metabolism needs to be clarified, and the safety of using the hormone long term needs to be established.

The way that Lawson’s and many other studies have been conducted is by putting oxytocin in a nasal spray and attempting to shoot it directly toward the brain. But it’s not clear how much of the drug the person is actually getting through this kind of application, and researchers are still working on making it more precise. To answer some of these questions, Lawson is currently conducting an NIH-funded randomized controlled trial that will administer oxytocin to obese men and women for eight weeks.

Finally, even if all these studies are successful, it’s important to remember that there are myriad reasons—social, economic, biological, cultural—that people become obese, addicted to food, or addicted to other substances. An oxytocin treatment might only work for some of them, and even if it did, not all obese people desire to lose weight. “Its effectiveness may depend on the reason for why the obese individual is obese,” Olszewski says.

Still, a drug that helped even a fraction of America’s 93 million obese people would be a major breakthrough. If all this research bears results, many years from now, there may be another reason to love the love hormone.

Oxytocin may treat abdominal pain

Australian researchers have found a key to treating chronic abdominal pain may lie in a hormone that induces labour and encourages social bonding.

The researchers, led by The University of Queensland’s Professor Paul Alewood from and the University of Adelaide’s Dr Stuart Brierley, have developed a version of the hormone oxytocin to treat chronic abdominal pain associated with conditions such as irritable bowel syndrome.

Oxytocin is known as ‘the love drug’ for its ability to enhance social interactions including maternal behaviour, partnership and bonding.

Professor Alewood, from UQ’s Institute for Molecular Bioscience, said the molecule they had developed – a version of oxytocin with improved stability – showed significant potential in alleviating abdominal pain.

“It can potentially survive in the digestive tract until it reaches the gut,” he said.

“This molecule acts on oxytocin nerve receptors in the bowel, which display increased sensitivity in conditions such as irritable bowel syndrome.”

Professor Alewood said it had no effect on healthy gut tissue, which was an important advantage in drug development where minimising side effects is crucial.

Chronic abdominal pain is a major health problem, with irritable bowel syndrome alone affecting around 11 per cent of the Western population.

Despite the high number of sufferers, there are currently no drugs that directly treat abdominal pain.

Oxytocin spray boosts social skills in children with autism

Treatment with the hormone oxytocin improves social skills in some children with autism, suggest results from a small clinical trial. The results appeared today in the Proceedings of the National Academy of Sciences1.

Oxytocin, dubbed the ‘love hormone,’ enhances social behavior in animals. This effect makes it attractive as a potential autism treatment. But studies in people have been inconsistent: Some small trials have shown that the hormone improves social skills in people with autism, and others have shown no benefit. This may be because only a subset of people with autism respond to the treatment.

In the new study, researchers tried to identify this subset. The same team showed in 2014 that children with relatively high blood levels of oxytocin have better social skills than do those with low levels2.

In their new work, the researchers examined whether oxytocin levels in children with autism alter the children’s response to treatment with the hormone. They found that low levels of the hormone prior to treatment are associated with the most improvement in social skills.

“We need to be thinking about a precision-medicine approach for autism,” says Karen Parker, associate professor of psychiatry at Stanford University in California, who co-led the study. “There’s been a reasonable number of failed [oxytocin] trials, and the question is: Could they have failed because all of the kids, by blind, dumb luck, had really high baseline oxytocin levels?”

The study marks the first successful attempt to find a biological marker that predicts response to the t

herapy.

“This study is suggestive of a hormonal-based biomarker for oxytocin treatment, which makes sense and is a promising step forward,” says Adam Guastella, professor of psychology at the Brain and Mind Centre at the University of Sydney in Australia, who was not involved in the study.

Hormone help:

The researchers enrolled 34 children with autism, aged 6 to 12 years. Parents gave their children a nasal spray twice a day for four weeks; 16 children got a spray containing oxytocin, and 18 got a spray with placebo. (Two of the children in the oxytocin group later dropped out of the study.)

The researchers measured oxytocin levels in the children’s blood at the start and end of the trial. They assessed the children’s social skills using a parent questionnaire called the Social Responsiveness Scale (SRS) and used other tests to assess the drug’s effects on repetitive behaviors and anxiety levels.

Based on SRS scores alone, oxytocin treatment did not lead to a statistically significant improvement in social skills. But when the researchers built a statistical model that accounted for the children’s oxytocin levels at the trial’s start, they found that the children who received oxytocin improved more on the SRS than did those on the placebo. The children with the lowest initial blood levels of oxytocin generally showed the most improvement.

Some children who received the placebo also showed an improvement in their social skills. These children also showed a rise in oxytocin levels over the course of the study. This indicates that simply participating in the study boosted their oxytocin levels, and may underlie their improvement, Parker says. Boosting oxytocin levels in other ways — say, through a behavioral intervention — could also be beneficial, she says.

The treated children showed no decrease in repetitive behaviors or anxiety, suggesting that the findings are specific to social skills. The therapy had no serious side effects.

Looking ahead:

Oxytocin levels vary naturally among people, and may even change throughout the day. The researchers tried to mitigate some of this variability by drawing each child’s blood at roughly the same time each day.

Still, the change in oxytocin levels in the placebo group could be a result of natural variation and might not be meaningful, says Linmarie Sikich, associate director of the Duke Center for Autism and Brain Development in Durham, North Carolina, who was not involved in the study.

Researchers also note that the trial did not assess oxytocin’s long-term effects. “Should oxytocin be found effective, no one is going to use it for four weeks and stop. We have to make sure that long-term administration is safe,” says co-lead researcher Antonio Hardan, professor of psychiatry and behavioral sciences at Stanford University.

Confirming oxytocin’s effectiveness as an autism treatment requires larger, longer-term studies. With that goal in mind, Sikich and her colleagues have enrolled nearly 300 people with autism in a placebo-controlled 24-week trial of the hormone. The placebo and treatment groups will then receive treatment for another six months.

The team is measuring the participants’ blood levels of oxytocin before, during and after treatment. They are also monitoring factors that alter the expression of the oxytocin gene, and of other genes involved in the same pathway.

Oxytocin reduces caloric intake in men.

OBJECTIVE:

Preclinical studies indicate that oxytocin is anorexigenic and has beneficial metabolic effects. Oxytocin effects on nutrition and metabolism in humans are not well defined. It was hypothesized that oxytocin would reduce caloric intake and appetite and alter levels of appetite-regulating hormones. Metabolic effects of oxytocin were also explored.

METHODS:

A randomized, placebo-controlled crossover study of single-dose intranasal oxytocin (24 IU) in 25 fasting healthy men was performed. After oxytocin/placebo, subjects selected breakfast from a menu and were given double portions. Caloric content of food consumed was measured. Visual analog scales were used to assess appetite, and blood was drawn for appetite-regulating hormones, insulin, and glucose before and after oxytocin/placebo. Indirect calorimetry assessed resting energy expenditure (REE) and substrate utilization.

RESULTS:

Oxytocin reduced caloric intake with a preferential effect on fat intake and increased levels of the anorexigenic hormone cholecystokinin without affecting appetite or other appetite-regulating hormones. There was no effect of oxytocin on REE. Oxytocin resulted in a shift from carbohydrate to fat utilization and improved insulin sensitivity.

CONCLUSIONS:

Intranasal oxytocin reduces caloric intake and has beneficial metabolic effects in men without concerning side effects. The efficacy and safety of sustained oxytocin administration in the treatment of obesity warrants investigation.

Oxytocin Study for Alcohol Withdrawal

Background: We recently showed in a placebo-controlled trial (n=11) that oxytocin (OXY) (24 IU insufflation bid) demonstrated efficacy in reducing withdrawal symptoms, anxiety and need for lorazepam in subjects with alcohol dependence undergoing detoxification (Pedersen et al, ACER 37:484, 2013).

Methods: The current pilot study tested for safety and efficacy of OXY compared to placebo (PBO) in subjects admitted to a residential community detoxification center. Effects on withdrawal and on subsequent drinking behavior, craving and anxiety were examined. Subjects with alcohol dependence and a history of withdrawal were enrolled within 48 hours of admission and received 4 insufflations of OXY (24 IU per dose) or PBO on Day 1, 3 doses on subsequent inpatient days and then bid dosing on outpatient days. Subjects were also recruited post-detox for the drinking trial and received similar dosing except no qid dosing on Day 1. Subjects were followed for 12 weeks as outpatients and received Medical Management.

Results: 115 subjects were prescreened to give 30 subjects fully screened to yield 19 randomized subjects. 8 subjects (4 OXY) form the detox inpatient group with the outpatient group consisting of 9 subjects (6 OXY) who completed at least 4 weeks of medication. Subjects receiving OXY during detox had a mean reduction in CIWA of 2.8 in the 48 hrs post-randomization vs an increase of 1.0 on PBO (p=.025) and used a mean of 2.25 mg lorazepam vs 5.25 mg lorazepam with PBO (p=.076). During the outpatient phase both the OXY and PBO groups had large reductions in heavy drinking days and large increases in abstinent days with decreased craving and anxiety but no significant OXY/PBO differences were found. No serious adverse events were seen, 2 OXY subjects complained of nose irritation and 2 subjects stopped meds (1 PBO for hives and 1 OXY for burning in the nose).

Conclusions: The finding of a significant reduction in alcohol withdrawal symptoms with less lorazepam use in the OXY vs PBO condition is compatible with our initial trial and is of therapeutic interest given that OXY does not have the deleterious profile of sedation and addiction liability associated with the benzodiazepines. The failure to find an OXY vs PBO effect on drinking behavior, anxiety or craving post-detox is difficult to interpret given the limited power of the trial. Tolerability of OXY was reasonable. Additional OXY trials in alcohol dependence are warranted.

In the future, there will be a pill for falling in love

Oxytocin could help treat alcohol use disorder

Oxytocin could help treat alcohol use disorder

by Public Library of Science

Oxytocin
Spacefilling model of oxytocin. Created using ACD/ChemSketch 8.0, ACD/3D Viewer and The GIMP. Credit: Wikipedia.

The neuropeptide oxytocin blocks enhanced drinking in alcohol-dependent rats, according to a study published April 16 in the open-access journal PLOS Biology led by Drs. Tunstall, Koob and Vendruscolo of the National Institutes of Health, and Drs. Kirson and Roberto of The Scripps Research Institute. Targeting the oxytocin system, the authors note, may provide novel pharmaceutical interventions for the treatment of alcohol-use disorder.

Administering oxytocin can decrease consumption, withdrawal symptoms, and drug-seeking behavior associated with several drugs of abuse, and shows promise as a pharmacological approach to treat drug addiction. But first, researchers need to understand how oxytocin mediates these effects in animal models.

To address this question, Tunstall and colleagues tested the hypothesis that oxytocin administration could normalize the maladaptive brain changes that occur in alcohol dependence and thereby reduce alcohol drinking in an established rat model of alcohol dependence.

The authors investigated oxytocin’s effects on dependence-induced alcohol consumption and altered signaling of the inhibitory neurotransmitter GABA in the central nucleus of the amygdala (CeA)—a key brain region in the network affected by alcohol dependence.

The experiments demonstrated that oxytocin administered systemically, intranasally or into the brain blocked excess drinking in alcohol-dependent but not in normal rats. Moreover, oxytocin blocked GABA signaling in the CeA. Taken together, these results provide evidence that oxytocin likely blocks enhanced drinking by altering CeA GABA transmission.

These results provide evidence that aberrations in the oxytocin system may underlie alcohol use disorder and that targeting this system, possibly by intranasal administration, could prove a promising therapy in people who misuse alcohol.

NAD+ IV Therapy | 703-844-0184 | Northern Virginia, Fairfax, Va | Ketamine Therapy Center for depression | NAD for aging and depression | What is NAD?

What is NAD+?

Nicotinamide adenine Dinucleotide is an essential molecule that participates in energy exchanges and metabolism throughout our body. It is a building block of energy exchange in a healthy body and brain.

Why is NAD+ Important?

NAD+ levels decline with age as well as in stressful conditions such as depression, addiction, infections, and other medical illness. This results in poor neurological and physical functioning seen in aging. Replacement of NAD+ increases clarity of mind, focus, concentration, improved energy, elevated mood, decreased anxiety, and fewer cravings.

What does NAD + do in the Body?

NAD+ is used in the production of energy as an electron transporter in metabolism. DNA Repair requires NAD+ to activate PARPs, which detect and repair damaged DNA. Gene Expression: Sirtuins are NAD dependent enzymes that regulate gene expression, increase metabolism, extend cell life, and prevent neurodegeneration. NAD+ also functions as a neurotransmitter for cell-to-cell communications in smooth muscle and brain cells. NAD+ and NADH are used in alcohol metabolism and metabolism of lactate.

What is NAD Therapy?

High dose NAD + delivered IV bypasses the liver and digestive system and enters cells to increase gene expression and help repair DNA. Treatment lasts 3 to 8 hours per session and may require multiple sessions depending on the protocol and condition.

Conditions Treated by NAD+ Therapy:

• Substance Abuse

• Addiction – Alcoholism | Opioid Abuse Disorders

• Stress

• Depression

• PTSD

• Neurodegenerative Disorders | Anti-aging | Parkinson’s Disease

• Chronic fatigue

• Brain Fog Benefits of NAD + Therapy:

• Increased Energy

• Improved Mood

• Increased mental clarity

• Increased focus and concentration

• Reduced cravings and addiction

More About NAD+

NAD+ is short for Nicotinamide Adenine Dinucleotide. NAD+ is an essential coenzyme in the body that regulates cellular energy metabolism and mitochondrial function. The mitochondria are the powerhouse of the cell where energy is made and regulated. Mitochondrial health equals overall health and increasing NAD+ levels result in more efficient gene transcription, energy regulation, DNA repair, gene expression, and cell signaling. Improving NAD+ levels are now considered the pivotal process for improving cardiovascular health, weight management, anti-aging, cognitive function, and neuroprotection. NAD+ is the most important cellular co-factor for improvement of mitochondrial performance and energy. Chronic illness and diseases of aging result in depression, worsened stress, loss of health-span, and hopelessness. NAD+ therapy has been shown to be capable of dramatically reducing symptoms of these illnesses by boosting the body’s natural cell repair. In addition to chronic illness, NAD+ has been used to treat chronic stress, depression, and anxiety. Dr. Sinclair published a groundbreaking paper which found that increasing NAD+ levels in older mice made the mitochondria of a 2 years old mice resemble those of a 6-month-old mouse when evaluated for critical biochemical markers of muscle health. Similar results of improved markers of aging have been seen in humans infused with NAD+, in which mitochondria appear to be rejuvenated. Scientists have shown that mice fed a high fat diet and then had their levels of NAD+ increased gained 60% less weight than mice on the same high fat diet without the NAD+ levels increased. As organisms age, their NAD+ levels decline. Dysfunctional cellular energy metabolism in mitochondria is increasingly implicated in diseases of aging, autoimmune disease, muscle wasting, neuropathies and other conditions. NAD+ therapy seems to reverse these conditions of aging by allowing Sirtuins to access DNA transcription and repair. NAD+ has a favorable profile on enhanced mitochondrial functioning and protects against age related axonal degeneration. This may be part of the reason for the positive impact in the treatment of patients with Reflex Sympathetic Dystrophy, Parkinson’s Disease and Alzheimer’s Disease.

Nicotinamide adenine Dinucleotide is an essential molecule that participates in energy exchanges and metabolism throughout our body. It is a building block of energy exchange in a healthy body and brain. Why is NAD+ Important? NAD+ levels decline with age as well as in stressful conditions such as depression, addiction, infections, and other medical illness. This results in poor neurological and physical functioning seen in aging. Replacement of NAD+ increases clarity of mind, focus, concentration, improved energy, elevated mood, decreased anxiety, and fewer cravings. What does NAD + do in the Body? NAD+ is used in the production of energy as an electron transporter in metabolism. DNA Repair requires NAD+ to activate PARPs, which detect and repair damaged DNA. Gene Expression: Sirtuins are NAD dependent enzymes that regulate gene expression, increase metabolism, extend cell life, and prevent neurodegeneration. NAD+ also functions as a neurotransmitter for cell-to-cell communications in smooth muscle and brain cells. NAD+ and NADH are used in alcohol metabolism and metabolism of lactate. What is NAD Therapy? High dose NAD + delivered IV bypasses the liver and digestive system and enters cells to increase gene expression and help repair DNA. Treatment lasts 3 to 8 hours per session and may require multiple sessions depending on the protocol and condition. Conditions Treated by NAD+ Therapy: • Substance Abuse • Addiction – Alcoholism | Opioid Abuse Disorders • Stress • Depression • PTSD • Neurodegenerative Disorders | Anti-aging | Parkinson’s Disease • Chronic fatigue • Brain Fog Benefits of NAD + Therapy: • Increased Energy • Improved Mood • Increased mental clarity • Increased focus and concentration • Reduced cravings and addiction More About NAD+ NAD+ is short for Nicotinamide Adenine Dinucleotide. NAD+ is an essential coenzyme in the body that regulates cellular energy metabolism and mitochondrial function. The mitochondria are the powerhouse of the cell where energy is made and regulated. Mitochondrial health equals overall health and increasing NAD+ levels result in more efficient gene transcription, energy regulation, DNA repair, gene expression, and cell signaling. Improving NAD+ levels are now considered the pivotal process for improving cardiovascular health, weight management, anti-aging, cognitive function, and neuroprotection. NAD+ is the most important cellular co-factor for improvement of mitochondrial performance and energy. Chronic illness and diseases of aging result in depression, worsened stress, loss of health-span, and hopelessness. NAD+ therapy has been shown to be capable of dramatically reducing symptoms of these illnesses by boosting the body’s natural cell repair. In addition to chronic illness, NAD+ has been used to treat chronic stress, depression, and anxiety. Dr. Sinclair published a groundbreaking paper which found that increasing NAD+ levels in older mice made the mitochondria of a 2 years old mice resemble those of a 6-month-old mouse when evaluated for critical biochemical markers of muscle health. Similar results of improved markers of aging have been seen in humans infused with NAD+, in which mitochondria appear to be rejuvenated. Scientists have shown that mice fed a high fat diet and then had their levels of NAD+ increased gained 60% less weight than mice on the same high fat diet without the NAD+ levels increased. As organisms age, their NAD+ levels decline. Dysfunctional cellular energy metabolism in mitochondria is increasingly implicated in diseases of aging, autoimmune disease, muscle wasting, neuropathies and other conditions. NAD+ therapy seems to reverse these conditions of aging by allowing Sirtuins to access DNA transcription and repair. NAD+ has a favorable profile on enhanced mitochondrial functioning and protects against age related axonal degeneration. This may be part of the reason for the positive impact in the treatment of patients with Reflex Sympathetic Dystrophy, Parkinson’s Disease and Alzheimer’s Disease.

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Weekly Ketamine Infusions Show Initial, Repeated Depression Benefits

A new study shows that weekly ketamine infusions are associated with continued and maintained reductions in depressive symptoms among patients with treatment-resistant depression.

The findings, which are considered novel among studies assessing ketamine administration for patients with treatment-resistant depression, evidence the promising role the controversial drug could play in psychiatric care.

A team of investigators, led by Jennifer L. Phillips, PhD, an associate scientist in the Mood Disorders Research Unit at The Royal’s Institute of Mental Health Research, conducted a randomized, double-blind crossover comparison of single ketamine infusion versus active placebo control midazolam. The assessment, held with 41 participants with treatment-resistant depression at single treatment center, observed patients receive 6 open-label ketamine infusions 3 times per week over 2 once patients had a relapse of depressive symptoms.

Patients who reported a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale (MADRS) received another 4 additional infusions once weekly in a maintenance phase.

Those administered a single ketamine infusion reported significantly reduced depressive symptoms at the primary efficacy endpoint of 24 hours post-care versus those treated with midazolam. The therapy showed cumulative antidepressant effects over repeated infusions, as well a doubling of antidepressant response rate in patients, according to linear mixed models.

Investigators found that 59% of patients met the response criteria following repeated infusions, with 3 infusions serving as the median dosage required to reach achieved response. In patients receiving weekly maintenance infusions, no further improvement in MADRS scores were reported.

The first-of-its-kind findings come just 1 month following the US Food and Drug Administration (FDA) approval of esketamine nasal spray (Spravato) for the treatment of patients with treatment-resistant depression. At the time, the therapy made history as the first novel treatment indicated for depression in 30 years—and headlines as one of the first hallucinogenic drugs to reach indication for a common condition.

Dennis Charney, MD, Dean of Icahn School of Medicine at Mount Sinai and a member of the Yale University team that led pioneering antidepressant ketamine trials in the 1990s, told MD Magazine® that microdosing or implementing controversial therapies for psychiatric care require what any other trial requires: control, safety, and a carefully-assessed standard for efficacy.



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Suboxone: Side Effects, Dosage, Uses, and More –– https://www.healthline.com/health/cdi/suboxone

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NOVA Health Recovery | Alexandria, Va 22306 | Call for esketamine and nasal ketamine as well as IV Ketamine for depression, PTSD, anxiety  703-844-0184 < Link

‘Nothing less than transformational:’ Ketamine brings relief to people with severe depression

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Ketamine gave Rachel Morgan her life back.

The 33 year old has struggled to beat back severe depression and post-traumatic stress disorder for much of her life. She’s tried more than 30 psychiatric medications, none of which helped. Her inner pain reached a level so unbearable that she retreated from the world. She stayed in bed. She stopped doing the dishes and taking out the trash, which piled up in her San Francisco apartment. She stopped socializing.

She lost the will to live.

“I had gotten to a point where I disappeared, mentally and physically,” Morgan said. “My psychiatrist kind of put his hands up in the air and said, ‘There’s nothing else I can do for you.'”

But he did suggest something different she could try, albeit not through him: ketamine. The only legally available psychedelic in the U.S., the drug is widely used as an anesthetic in hospitals and medical settings. But it has been found to give people with severe mood disorders, including treatment-resistant depression and suicidal ideation, almost unbelievably fast-acting relief from their symptoms — some with a single dose, though more commonly it takes several treatments.

Morgan received her first ketamine infusion in a Palo Alto psychiatry clinic in June. By her second treatment, she took out the trash for the first time in months. After several infusions, friends told her she was talking more than she had in a year.

For the first time in her life, “I felt like there is a future for me,” Morgan said. “It’s left me a different person than I was a year ago.”

Ketamine is starting to shed its reputation as a psychedelic club drug and experimental mental health treatment as more patients like Morgan see results and more research is conducted on the drug’s impact on the brain. A watershed moment came in March when the U.S. Food and Drug Administration (FDA) approved Spravato, or esketamine, a ketamine nasal spray for adults with treatment-resistant major depression. One short-term clinical trial showed the spray had a statistically significant effect on depression compared to a placebo, and patients saw some effect within two days, according to the FDA.

A handful of local private psychiatry clinics, including in Palo Alto, Menlo Park and Woodside, have in recent years started offering ketamine. They are working at the forefront of a promising new treatment in psychiatry, a field that has seen little medication innovation for decades.

Many of the psychiatrists who run these clinics said they were initially skeptical of the drug’s potential, with little still known about how exactly ketamine works as an antidepressant and its long-term effects, but became believers when they saw life-changing improvements in patients for whom nothing else had worked.

“I think we’re on the brink of an amazing revolution in psychiatry,” said Alex Dimitriu, who offers ketamine treatments at his Menlo Park private psychiatry clinic. “We’re on the brink of understanding that a lot of drugs that previously we thought were drugs of abuse are actually turning out to be some very powerful agents.”

Exploring ketamine’s potential

Ketamine was developed in 1962 as a fast-acting anesthetic and continues to be widely used as such today, particularly for surgery and pain relief, including with children and in veterinary medicine. The drug is a schedule III controlled substance, meaning its medical use is accepted and it has moderate to low potential for abuse. The World Health Organization has included ketamine on its list of essential medicines since 1985 and calls it “possibly the most widely used anesthetic in the world.” As an anesthetic, it is incredibly safe (it does not depress breathing or blood pressure) and is easy to administer, according to the World Health Organization.

In higher doses, ketamine produces a “dissociative” state that can include hallucinations and out-of-body experiences. The drug’s conscious-altering potential led to its recreational use in the psychedelic era of the 1960s and 1970s.

Reports of ketamine use to treat psychological or psychiatric disorders first emerged in the 1970s, including in Argentina, Mexico and Russia, according to a study co-authored by Jennifer Dore, who offers ketamine at her private Helios Psychiatry practice in Woodside.

In 2000, a group of Yale University researchers published a seminal but small-scale study that found seven patients with major depression who received ketamine showed significant improvement in their symptoms within 72 hours, suggesting the drug could be used as an antidepressant.

Six years later, a National Institute of Mental Health study showed that ketamine reduced depression symptoms more quickly than a placebo.

Dore, who trained as a resident at the Stanford University Department of Psychiatry, became curious about ketamine several years ago while treating patients with severe PTSD and treatment-resistant depression. They simply weren’t getting better.

Dore dug into the available research on the drug’s antidepressant effects, which suggested that ketamine inhibits the action of the brain’s NMDA receptors and triggers glutamate production, which causes the brain to form new neural connections. She reached out to Phil Wolfson, director of the Center for Transformational Psychotherapy in San Anselmo, who pioneered ketamine-assisted psychotherapy, in which ketamine is administered while simultaneously patients receive therapy. She was compelled by taking this approach rather than the more medical model of providing the drug in isolation.

The results with her early patients in 2016 were like nothing she had ever seen.

“They had immediate relief,” she said.

Dore said her clinic was the first on the Peninsula to offer ketamine-assisted psychotherapy. She now offers trainings for other providers and sits on the board of the Ketamine Research Foundation.

In March, Dore published a five-year study with two other psychiatry practices that found patients who received ketamine saw clinically significant improvements in depression and anxiety, particularly so for people who came in with more severe symptoms like suicidality and a history of psychiatric hospitalization. At their clinics, they saw the drug help people suffering from obsessive compulsive disorder, bipolar disorder, personality disorders, substance abuse, psychological reactions to physical illness and even relationship issues and social anxiety.

“Ketamine promotes a time-out from (the) ordinary, usual mind, relief from negativity, and an openness to the expansiveness of mind with access to self in the larger sense,” Dore’s study states. “These effects enhance a patient’s ability to engage in meaningful psychotherapy during and after administration.”

Dore is a staunch champion of combining ketamine with psychotherapy, which she believes is necessary to harness the full potential of the drug. She doesn’t see ketamine as a magic bullet, but rather one tool she can use in concert with others — talk therapy, medication, nutrition — to treat people in serious psychological pain.

Before patients start ketamine, Dore carefully evaluates them to determine if it’s an appropriate next step in their treatment, as recommended by the American Psychiatric Association, including through therapy sessions, psychological tests and a review of their medical history. If they choose to proceed, Dore requires patients to sign a lengthy consent form that explains how ketamine works and its potential benefits and risks.

During a patient’s initial treatment, Dore monitors their physical and emotional responses, including blood pressure and heart rate, to decide on an appropriate dose going forward. The highest doses can produce the dissociative state, or the dream-like sensation of disconnecting from reality, Dore said. (Some people believe they have died and are in a new reality, she said. One patient described it as being in a lucid dream.) At lower doses, it can feel more like having a glass of wine, she said. The peak effects last about 15 to 30 minutes, according to Dore.

Patients can take the ketamine via a small lozenge that dissolves under their tongues, intravenously or an intra-muscular injection.

They receive the ketamine in a large second-floor space at Dore’s practice. It resembles a homey living room more than a psychiatric setting — a reflection of the importance of creating “set and setting” for a psychedelic experience, including a comforting physical environment. A large, soft corner couch is strewn with pillows, including one that says “anger” and another, “love.” During treatments, Dore pulls down the blinds on the windows, adjusts the temperature and offers patients weighted blankets, eyeshades and quiet music. The sessions last two to three hours.

Gaining a new perspective

Andy Mathis was at the end of his mental rope when he found Dore. A father, husband and successful tech industry executive, he had quietly suffered from self-doubt and insomnia since he was a young child. By the time he reached his mid-40s, it had escalated to depression. He felt his well-being and very brain chemistry was at risk.

A friend of a friend referred him to Dore, who prescribed him antidepressant and anti-anxiety medications that finally helped him sleep. But she suspected there was more to understand about the root causes of his symptoms, he said, and suggested ketamine as a means for exploring that.

A former professional tennis player, Mathis said he had never taken any drugs before. He did his own research on ketamine and thought it sounded “groundbreaking.” He was more curious than fearful about embarking on a psychedelic experience.

He received his first infusion two and a half years ago and continues to get ketamine every four to eight weeks today.

“It was indeed transformational,” Mathis said. “Nothing less than transformational.”

Mathis described the experience as taking him out of his own ego, a “tilt(ing) of the prism on how I see things.”

“It allowed me to have a detached, philosophical view on all things — me, my place in the world, my relationships,” he said.

This helps him make sense of his emotions “in a way that can be extremely difficult and sometimes even impossible to do when I am inside of myself,” referring to his default, day-to-day mental state.

Over the course of the infusions, Mathis started feeling more comfortable in his own skin, which he said improved his relationships and even his work performance. He realized he has a love for music and at age 47, started to learn how to play the saxophone. He came to a better understanding of his relationship to food and how he had used it as a coping mechanism.

Combining the ketamine-induced realizations with therapy was crucial, Mathis said.

“It was the post-experience discussions that we would have that would also unravel and unwind some of the unhealthy habits,” he said. “I’m 47 now, almost 48. I am healthier now than I was probably, maybe, ever.”

Dore likened ketamine’s power as a catalyst for psychological change to “a year of psychotherapy in three hours.”

Unlike antidepressants, patients don’t have to take ketamine every day and do not experience significant side effects; they can become nauseous or slur their words during the treatment, psychiatrists said. They require patients to have someone to drive them home after the treatment.

Mathis, for his part, did not experience any negative side effects. A patient at another local psychiatry clinic, Lisa Ward, however, said her mind feels “foggy” if she has two infusions in a single week. According to the FDA, the most common side effects experienced by patients treated with Spravato, the esketamine nasal spray, in clinical trials including disassociation, dizziness, nausea, lethargy and increased blood pressure.

“It would be inhumane,” Dore said, to not offer ketamine to people in intractable mental anguish. “We need things that are transformative, that aren’t putting a Band-Aid on a problem.”

Psychiatrist calls it ‘life-changing’

When Rameen Ghorieshi first looked into ketamine as an option for a patient with treatment-resistant depression about five years ago, it was still “very much fringe,” he said. His colleagues at Stanford, where he completed his psychiatric training, knew about the drug but had no idea how to actually use it as a treatment.

He decided to offer ketamine at his small private practice in downtown Palo Alto, Palo Alto Mind Body. He trained with an anesthesiologist and started with two patients. One suicidal young woman who had dealt with a chronic illness since childhood and didn’t intend to live past 30 years old, he said, got to the point where she was working four days a week, socializing and planning to go back to school.

“That just blew my mind,” Ghorieshi said. “I knew it would help just reading the studies but seeing it firsthand was pretty incredible.”

He has done more than 1,000 ketamine infusions at his downtown Palo Alto practice. Eighty-seven percent of patients rated their improvements as significant and 35% of those described it as “life-changing.” It particularly helped suicidal patients, he said. About 13% of patients said the improvement in their symptoms was not worth the time and effort of the infusions.

“This is a bit of a departure for me. I’m a very conservative prescriber,” Ghorieshi said. “My patients tend to be on one, two, maybe three medications. … But it was so remarkable that it seemed hard not to offer it to people.”

Ghorieshi said his was the first clinic in the Bay Area to treat someone with the tightly controlled, FDA-approved nasal spray. A handful of his patients have since received it, with good results, he said.

Esketamine is attached to a federal Risk Evaluation and Mitigation Strategy, which the FDA “can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks.” Providers and patients must register and the drug must be administered in a certified medical office under the supervision of a health care professional.

At Palo Alto Mind Body, patients receive eight ketamine infusions over several weeks. They are strongly encouraged to also pursue therapy but it’s not part of the treatment itself, Ghorieshi said.

He or a nurse supervises patients over the course of the 90-minute appointments. Morgan likes to sit upright on the couch in Ghorieshi’s office, covered by a blanket that keeps her warm and gives her a sense of emotional security. She listens to relaxing elevator music. After, she goes home and naps off the residual effects.

Years ago, she was given much higher doses of ketamine as a pain treatment for chronic physical illnesses and had horrible hallucinations, which she described as “having my head slammed against a wall repeatedly by a slime monster from a deep black bog.”

At the dose Ghorieshi gives her, she feels like the floor and ceiling switch. Her inhibitions dissolve. Afterwards, she feels more open to trying new experiences, from coping mechanisms for her depression to new foods. She feels her perfectionism, which for a long time had prevented her from being vulnerable with others, soften.

“To me, that’s the magic of ketamine,” Menlo Park psychiatrist Dimitriu said of the drug’s tendency to destabilize entrenched behaviors. “I think that speaks to the magic of future psychedelic research, which is down the pipeline, in that it increases our openness to new experience. The general belief here is if you’re depressed severely, you get stuck in maladaptive patterns.”

Lisa Ward didn’t see immediate relief from her life-long depression after her first ketamine infusion with Ghorieshi in March.

Then, a week later as the drug continued to work in her system, “the whole cloud just lifted,” she said. (It takes most patients several treatments to see results, according to Ghorieshi.)

She had more energy. She felt more productive. The benefits extended to her loved ones, as she’s engaged more with her two young children, husband, her parents and her sister.

“It’s enough for me to have more fun with my kids. It’s enough for me to spend more time with my husband instead of going to bed because I just can’t deal with the day anymore,” she said. “Being in depression you don’t realize it but it takes a big toll on other people.”

For Ward, a photographer, the effects of ketamine last about five weeks before she feels the cloud returning. There was one period where the ketamine seemed to stop working all together. Because she lives in Hollister — a three-hour round trip drive from Palo Alto, not including the time of the session itself — and pays out of pocket for the expensive treatment, gaps between her appointments stretch longer than she’d like.

She actually doesn’t enjoy the experience of being on ketamine, which she described as mind-bending and often intense. But she said the disruption of her depression allows her to focus on shifting the underpinning behavior and thought patterns.

Ketamine “doesn’t magically lift all … your problems away,” Ward said. “You’re more apt to make changes when you’re thinking clearly and you’re not so focused on the depression.”

While esketamine, the nasal spray, is covered by insurance because of the FDA approval, most other ketamine administrations are not. Morgan pays almost $1,000 out of pocket for each infusion, though Ghorieshi said some of his patients have been reimbursed for their treatments. Dore charges patients for her time as a provider, about $1,000 for a several-hour session, rather than for the drug itself.

Morgan felt strongly about using her full name in this article to dispel stigma around ketamine in the hopes it will be more widely accepted — and thus available to more people in need.

“Just because you hear something in one context, like ketamine being used as an illicit drug, doesn’t mean it doesn’t exist in another,” she said. “I think that’s what scares insurance companies away from covering it for patients. And that’s what makes me angry because I wish this treatment was out there for everybody to see. I’m lucky enough to be able to handle the financial portion, but the average person might not be.”

The as-yet-unknown risks

Despite the success stories, ketamine has not yet been fully accepted by the broader psychiatric community. The unanswered questions and possible risks that surround ketamine — how it works as an antidepressant, the long-term effects, the potential for abuse — are cause for caution, said Alan Schatzberg, a Stanford School of Medicine psychiatry professor and former president of the American Psychiatric Association.

“Rarely has there been so much anticipation for a new antidepressant as has been seen for intranasal esketamine,” he wrote in the American Journal of Psychiatry in May about the newly FDA-approved ketamine nasal spray.

“Do we have clear evidence of efficacy? Maybe. How strong is the efficacy? Apparently mild. Do we have a real sense of how long and how often to prescribe it? It’s not entirely clear.

“Taken together,” he wrote, “there are more questions than answers with intranasal esketamine, and care should be exercised in its application in clinical practice.”

In an interview, Schatzberg said he’s concerned about repetitive, extended use of any form of ketamine and the drug’s potential for dependence. The American Psychiatric Association has said that the literature on ketamine’s longer-term effectiveness and safety is so limited that the organization cannot “make a meaningful statement” on such use.

“The scarcity of this information is one of the major drawbacks to be considered before initiating ketamine therapy for patients with mood disorders and should be discussed with the patient before beginning treatment,” an American Psychiatric Association task force wrote in a consensus statement on ketamine in 2017.

Schatzberg co-authored a 2018 study that suggests ketamine’s antidepressant effects are tied to the brain’s opioid system and said the implications of this for dependency should be studied further.

“This is the same as any potential drug of abuse, any kind of opioid type drug. Serial use is less the issue. It’s when you get into repetitive use that one needs to be careful,” Schatzberg said. “That’s the clarion call that we’ve been sounding.”

One of his study co-authors, Carolyn Rodriguez, a Stanford associate professor of psychiatry and behavioral sciences, has been blown away by the rapid benefits of ketamine in studies she’s conducted with patients with obsessive compulsive order, or OCD. In the first-ever randomized clinical trial of ketamine compared to placebo in OCD, she found that a single low dose of ketamine prompted a decrease in OCD symptoms within hours for all participants.

Yet she remains cautious and said more research is needed to fully understand the powerful drug. She’s currently studying the mechanisms of how ketamine works so quickly on OCD patients, with funding from the National Institute of Mental Health.

“I believe that the state of the field of ketamine and how it works on OCD is not at the point yet where I would recommend it clinically because I always like to see science, (including) my own science, replicated,” Rodriguez said.

With pause about the long-term effects, she and other researchers have suggested a national registry be created to monitor side effects.

Ghorieshi said he is frank with his patients about the unknowns and potential downsides of ketamine, which must be weighed against other risks.

“We do know the immediate mortality and morbidity of things like suicide and depression.

I think that’s, as with anything, the risk-benefit. What are the risks of suicide, but also depression and anxiety in general?” he said. “You have to balance that versus these unknown risks of ketamine.”

Mathis, for his part, said he’s not concerned about the long-term effects of taking ketamine.

“What I worry about,” Mathis said, “is what my health would have done without it.”

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Mindfulness-Based Prevention Outcomes for Cocaine Dependence Improved by Ketamine Injection

A single ketamine infusion improved several treatment outcomes in adults with cocaine dependence who were engaged in mindfulness-based behavior modification, according to study data published in the American Journal of Psychiatry.

Individuals seeking treatment for cocaine dependence (n=55) were randomly assigned to receive a 40-minute intravenous infusion of either ketamine (0.5 mg/kg) or midazolam (0.025 mg/kg) as part of a five-week trial. Patients were hospitalized for five days in a psychiatric research unit, during which time they received daily sessions of mindfulness-based relapse prevention. On day 2, patients received their infusion; on day 5, they were discharged. Patients then attended twice-weekly follow-up visits for four weeks, at which they continued their sessions and were assessed for various clinical variables. Cocaine use after discharge was assessed via patient interview and urine toxicology screening. A six-month follow-up interview was also conducted by telephone.

Demographic and clinical variables were similar in patients who received ketamine (n=27) and patients who received midazolam (n=28). Route of cocaine ingestion was controlled for in all analyses. A total of 48.2% of patients in the ketamine group remained abstinent during the last two weeks of the trial compared with 10.7% of the midazolam group. The odds of end-of-study abstinence in the ketamine group was nearly six times that in the midazolam group (odds ratio, 5.7; 95% CI, 1.3-25.1; =.02). Per Cox regression analysis, the ketamine group was 53% less likely to relapse compared with the midazolam group (hazard ratio, 0.47; 95% CI, 0.24-0.92; =.03). In addition, craving scores were 58.1% lower in the ketamine group than in the midazolam group (=.01). At the six-month telephone follow-up interview, 12 patients (44%) in the ketamine group reported abstinence compared with none in the midazolam group. The percentage of abstinent individuals was significantly associated with treatment group (<.001). 

A single ketamine infusion was associated with significantly improved treatment outcomes compared with midazolam in a cohort of adults with cocaine dependence. Further research in a larger sample is needed to confirm these findings.

Reference

Dakwar E, Nunes EV, Hart CL, et al. A single ketamine infusion combined with mindfulness-based behavioral modification to treat cocaine dependence: a randomized clinical trial [published online June 24, 2019]. Am J Psychiatry. doi:10.1176/appi.ajp.2019.18101123

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Ketamine could be first of new generation of rapid acting antidepressants, say experts

Ketamine is the first truly new pharmacological approach to treating depression in the past 50 years and could herald a new generation of rapid acting antidepressants, researchers have predicted.

“We haven’t had anything really new for about 50 or 60 years,” said Allan Young, professor of mood disorders at the Institute of Psychiatry, Psychology and Neuroscience at King’s College, London, at a briefing on 12 July at London’s Science Media Centre.

Most of the new launches have been “tinkering with drugs which were really discovered in the ’50s and ’60s,” he explained. “Even the famous Prozac, which came in in the late ’80s, is really just a refinement of the tricyclic antidepressants that came in the ’50s. People say we are still in the age of steam, and we need to go to the next technological advance.”

Slow onset

In the past few years the focus has fallen on ketamine, which is used for pain relief and anaesthesia but is better known for being a horse sedative and a “club drug” that can induce hallucinations and calmness. It has been found to have rapid antidepressant effects and to be effective in many patients with treatment resistant depression.

US clinics increasingly offer IV infusions of ketamine off label, and in March esketamine, a nasal ketamine based drug, was approved by the US Food and Drug Administration for treatment resistant depression,1 at a cost of £32 400 (€36 060; $40 615) per patient per year.

Carlos Zarate, chief of the Experimental Therapeutics and Pathophysiology Branch at the US National Institute of Mental Health, who has been a key figure in the discovery and evaluation of ketamine as an antidepressant, said that one of the main problems with current antidepressants was their speed of onset in terms of antidepressant and anti-suicidal effects.

He explained that it took 10-14 weeks to see significant improvement with monoaminergic based antidepressants. “In my mind that is too slow,” he said. “We are focusing on treatments that can produce results within hours. That is where we are heading with the next generation of antidepressant, and ketamine is now the prototype for future generation antidepressants which will have rapid, robust antidepressant effects—rapid within a few hours.”

Efficacy and tolerability

Zarate said that, besides correcting chemical imbalances of serotonin and norepinephrine, the new generation of ketamine based antidepressants had other effects such as enhancing plasticity and restoring the synapses and dendrite circuits that shrivel in depression.

When ketamine is given to patients it binds to the N-methyl-D-aspartate (NMDA) receptor, causing a series of transient side effects including decreased awareness of the environment, vivid dreams, and problems in communicating. But the half life of ketamine is only two to three hours, so these side effects quickly subside, whereas the therapeutic effects of the drug last seven days or longer.

Zarate’s team is now focusing on the 24 metabolites of ketamine to hone the drug’s efficacy and tolerability. One of these, hydroxynorketamine, has already been shown to have similar antidepressive effects to ketamine in animals, without the side effects, and it is due to be tested in patients this autumn.

“Ketamine may actually be a prodrug for hydroxynorketamine,” said Zarate.

High cost

A few dozen patients with treatment resistant depression have been treated with ketamine in UK trials, and the European Medicines Agency and the Medicines and Healthcare Products Regulatory Agency are due to reach a decision on authorising esketamine for marketing in October. If the drug is approved private clinics will be able to provide it. But it would be unlikely to be available through the NHS until at least 2020, if at all, as the National Institute for Health and Care Excellence would need to deem it cost effective.

Rupert McShane, consultant psychiatrist and associate professor at the University of Oxford, said that, as well as the likely high cost of esketamine, patients treated with it must be observed in a clinic for two hours after each administration. This would require substantial clinical time, as esketamine is given twice a week for the first month, once a week for the second month, and once a week or once a fortnight from then on.

McShane also recommended that, if approved, a multidrug registry should be set up to monitor the long term safety and effectiveness of ketamine based drugs. Patients would be asked to input their use of any prescribed ketamine, esketamine, or any other future ketamine based product, as well as any self medication with illicit ketamine.

References


    1. Silberner J
    . Ketamine should be available for treatment resistant depression, says FDA panel. BMJ2019;364:l858.doi:10.1136/bmj.l858 pmid:30796014FREE Full TextGoogle Scholar

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Ketamine Study Reveals How to Make It an Even Better Depression Treatment

In early March, the FDA approved a nasal spray for depression based on ketamine, a substance once known only as a rave drug. Despite its reputation, ketamine is so promising as an anti-depressant that it will soon be available in licensed clinics throughout the country. A study published in Science on Thursday proposes the new treatment can be made even better.

In their paper, a team of scientists at Weill Cornell’s Medicine’s Feil Family Brain and Mind Research Institute show that ketamine can help the brain reform synapses, crucial connections between neurons, that can alleviate depressive symptoms. Ketamine is already famous for working quickly to relieve depressive symptoms — within days or hours — co-author Conor Liston, Ph.D., tells Inverse, but maintaining those crucial connections is key to extending its effects.

“Our study shows that the formation of new connections (synapses) between brain cells is required for sustaining ketamine’s antidepressant effects in the days after treatment,” says Liston, also professor of neuroscience at Weill Cornell. “Ketamine is an exciting new treatment for depression that differs from drugs like SSRIs in that it relieves symptoms rapidly. However, those effects are not always sustained.”

upset, depressed
Ketamine-based nasal spray is a new FDA-licensed drug for treatment-resistant depression.

Growing Back Dendritic Spines

In a mouse model, Liston and his co-authors demonstrated that doses of ketamine helped mouse brains regrow dendritic spines, small protrusions on neurons that help them pick up signals rom other cells that, crucially, degrade during exposure to chronic stress. These dendritic spines are a key part of synapse formation.

The degradation of these spines is not a perfect analog to human depression, but humans have them as well, and Liston points out that some of the most important features of depression in humans are also present in chronically stressed mice.

To create depression-like conditions, the team degraded the dendritic spines in their mice using stress hormones. Then, they gave one group a dose of ketamine, which they expected to have anti-depressive effects.

dendritic spine
A dendritic spine helps form a synapse — a connection to another neuron.

The dose of ketamine not only changed the mice’s behavior — they tried harder to escape their cages — it also helped reform the dendritic spines in their brains. Interestingly, the ketamine didn’t form random dendritic spines but actually seemed to replace the old ones that had been degraded by constant stress. Of the new spines formed, 47.7 percent grew within two micrometers of where the old ones once were.

Why Dendritic Spines Are Important

The new dendritic spines serve an important purpose in the mouse brains. Within three hours of treatment, previously damaged circuits in the prefrontal cortex were starting to come back online, but this happened before new synapses form. At the end of the experiment, an estimated 20.4 to 31.0 percent of the lost synapses were restored after the mice took ketamine.

The fact that the circuits were restored before the synapses reformed suggests that ketamine jump-starts a two-step process that fights depression. The first step is the rapid anti-depressant effect that is seen in so many studies. The second step — regrowing the spines and restoring synapses — occurs more slowly, which means it’s the one scientists should focus on if they’re looking to make ketamine’s effects on depression last longer, Liston says.

When Liston used blue light to artificially remove the newly grown spines in a follow-up experiment, the mice relapsed into depressive symptoms. It suggested that maintaining these dendritic spines is important in keeping depression at bay.

“Our results suggest that interventions aimed at enhancing the survival of newly formed connections in prefrontal brain circuits could be useful for augmenting ketamine’s antidepressant effects by increasing their durability in the days and weeks after treatments.”

The FDA’s approval of a ketamine-based drug to treat depression was groundbreaking in itself, especially since it works differently than other anti-depressant drugs. But just because it’s been approved doesn’t mean there aren’t ways to improve it. Depression can be alleviated with ketamine, but for now the illness constantly threatens individuals with remission. Preventing the potential for a relapse with the promise of longer-lasting effects is one way to make this already remarkable drug even more helpful.

tructured Abstract

INTRODUCTION

Depression is an episodic form of mental illness, yet the circuit-level mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood. Ketamine relieves depressive symptoms rapidly, providing an opportunity to study the neurobiological substrates of transitions from depression to remission and to test whether mechanisms that induce antidepressant effects acutely are distinct from those that sustain them.

RATIONALE

Contrasting changes in dendritic spine density in prefrontal cortical pyramidal cells have been associated with the emergence of depression-related behaviors in chronic stress models and with ketamine’s antidepressant effects. But whether and how dendritic spine remodeling is causally involved, or whether it is merely correlated with these effects, is unclear. To answer these questions, we used two-photon imaging to study how chronic stress and ketamine affect dendritic spine remodeling and neuronal activity dynamics in the living prefrontal cortex (PFC), as well as a recently developed optogenetic tool to manipulate the survival of newly formed spines after ketamine treatment.

RESULTS

The induction of depression-related behavior in multiple chronic stress models was associated with targeted, branch-specific elimination of postsynaptic dendritic spines and a loss of correlated multicellular ensemble activity in PFC projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predicted motivated escape behavior. Unexpectedly, ketamine’s effects on behavior and ensemble activity preceded its effects on spine formation, indicating that spine formation was not required for inducing these effects acutely. However, individual differences in the restoration of lost spines were correlated with behavior 2 to 7 days after treatment, suggesting that spinogenesis may be important for the long-term maintenance of these effects. To test this, we used a photoactivatable probe to selectively reverse the effects of ketamine on spine formation in the PFC and found that the newly formed spines play a necessary and specific role in sustaining ketamine’s antidepressant effects on motivated escape behavior. By contrast, optically deleting a random subset of spines unrelated to ketamine treatment had no effect on behavior.

CONCLUSION

Prefrontal cortical spine formation sustains the remission of specific depression-related behaviors after ketamine treatment by restoring lost spines and rescuing coordinated ensemble activity in PFC microcircuits. Pharmacological and neurostimulatory interventions for enhancing and preserving the rescue of lost synapses may therefore be useful for promoting sustained remission.

Why is ketamine an antidepressant?

A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine’s antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants.

Structured Abstract

INTRODUCTION

Depression is an episodic form of mental illness, yet the circuit-level mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood. Ketamine relieves depressive symptoms rapidly, providing an opportunity to study the neurobiological substrates of transitions from depression to remission and to test whether mechanisms that induce antidepressant effects acutely are distinct from those that sustain them.

RATIONALE

Contrasting changes in dendritic spine density in prefrontal cortical pyramidal cells have been associated with the emergence of depression-related behaviors in chronic stress models and with ketamine’s antidepressant effects. But whether and how dendritic spine remodeling is causally involved, or whether it is merely correlated with these effects, is unclear. To answer these questions, we used two-photon imaging to study how chronic stress and ketamine affect dendritic spine remodeling and neuronal activity dynamics in the living prefrontal cortex (PFC), as well as a recently developed optogenetic tool to manipulate the survival of newly formed spines after ketamine treatment.

RESULTS

The induction of depression-related behavior in multiple chronic stress models was associated with targeted, branch-specific elimination of postsynaptic dendritic spines and a loss of correlated multicellular ensemble activity in PFC projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predicted motivated escape behavior. Unexpectedly, ketamine’s effects on behavior and ensemble activity preceded its effects on spine formation, indicating that spine formation was not required for inducing these effects acutely. However, individual differences in the restoration of lost spines were correlated with behavior 2 to 7 days after treatment, suggesting that spinogenesis may be important for the long-term maintenance of these effects. To test this, we used a photoactivatable probe to selectively reverse the effects of ketamine on spine formation in the PFC and found that the newly formed spines play a necessary and specific role in sustaining ketamine’s antidepressant effects on motivated escape behavior. By contrast, optically deleting a random subset of spines unrelated to ketamine treatment had no effect on behavior.

CONCLUSION

Prefrontal cortical spine formation sustains the remission of specific depression-related behaviors after ketamine treatment by restoring lost spines and rescuing coordinated ensemble activity in PFC microcircuits. Pharmacological and neurostimulatory interventions for enhancing and preserving the rescue of lost synapses may therefore be useful for promoting sustained remission.



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Long known as a party drug, ketamine now used for depression, but concerns remain

A decades-old anesthetic made notorious as a party drug in the 1980s is resurfacing as a potential “game-changing” treatment for severe depression, patients and psychiatrists say, but they remain wary about potential long-term problems.

The Food and Drug Administration earlier this month OKd use of Spravato for patients with depression who have not benefited from other currently available medications. Spravato, the brand name given to the drug esketamine, is a molecule derived from ketamine — known as Special K on the club scene.

Ketamine has been shown in some studies to be useful for treating a wide variety of neurological disorders including depression. Regular, longtime use of it isn’t well understood, psychiatrists say, but the need for a new drug to treat depression is so great that the FDA put Spravato on a fast-track course for approval.

The drug likely will be commercially available in a few weeks, and patients already are requesting it. Restrictions around its use, though — the drug must be administered in a doctor’s office by providers who are certified with the company making it — mean it may be months before it’s widely available, and longer than that before insurers start paying for it.

“I don’t think we know at this point how effective it’s going to be,” said Dr. Craig Nelson, a psychiatrist at the UCSF Depression Center. “There have been a number of studies of ketamine, sometimes showing effects in people who were resistant to other drugs. If we can treat a different group of people, it would be a great advantage.”

Ketamine was developed in the 1960s as a surgical anesthetic for people and animals. The drug can cause hallucinations and a feeling of “dissociation” or unreality, and in the 1980s it took off as a party drug among people seeking those effects. It remained a common anesthetic, though, and in the early 2000s doctors began to notice a connection between ketamine and relief from symptoms of depression and other mood disorders.

Spravato is delivered by nasal spray, which patients give themselves in a doctor’s office. Patients must be monitored while they get the drug and for two hours after to make sure they don’t suffer immediate complications. At the start, patients will get the nasal spray twice a week for four weeks, then taper to regular boosters every few weeks for an indefinite period of time.

Studies of ketamine — and specifically of Spravato — have produced encouraging but inconsistent results. Psychiatrists say that, like most other antidepressants, the drug probably won’t help everyone with difficult-to-treat depression. But there likely will be a subset of patients who get substantial benefits, and that alone may make it an incredible new tool.

About 16 million Americans experience depression every year, and roughly a quarter of them get no benefit from antidepressants on the market. Thought scientists haven’t determined exactly how ketamine works on the brains of people with depression or other mood disorders, it appears to take a different path of attack than any drug already available. That means that people who don’t respond to other antidepressants may find this one works for them.

But a concern among some psychiatrists is that studies have suggested that ketamine may affect the same receptors in the brain that respond to opioids. Ketamine and its derivations may then put patients at risk of addiction — but research so far hasn’t explored that kind of long-term effect.

“There might be some potential problems if you used it too aggressively,” said Dr. Alan Schatzberg, director of the Stanford Mood Disorders Center, who led the research that identified a connection with opioid receptors. “The issue is not so much the short-term use, it’s the repetitive use, and the use over time, as to whether there are going to be untoward consequences.

“It would be hard for me to recommend the use of this drug for chronically depressed people without knowing what the endgame is here,” he added.

Dr. Carolyn Rodriguez, a Stanford psychiatrist who was part of the studies of ketamine and opioid receptors, said she shares Schatzberg’s concerns. But she’s been studying the use of ketamine to treat obsessive-compulsive disorder, and for some patients the results have been so remarkable that the benefits may exceed the risks.

“When I gave ketamine to my first patient, I nearly fell off my chair. Somebody said it was like a vacation from their OCD, and I was just, ‘Wow, this is really possible,’” Rodriguez said. “I want to make sure patients have their eyes wide open. I hope (the FDA approval) spurs more research, so we can really inform consumers.”

Though the new nasal spray is the first formal FDA approval of a ketamine-derived drug, psychiatrists have been using the generic anesthetic for years to study its effect on depression and other mood disorders.

In recent years, clinics have opened around the country offering intravenous infusions of ketamine to people with hard-to-treat depression and other problems. These treatments aren’t specifically FDA-approved but are allowed as off-label use of ketamine. The clinics have faced skepticism from some traditional psychiatrists, but there’s a growing ream of anecdotal evidence that the ketamine IVs work — for some people.

Aptos resident Mary, who suffers from depression and other mood disorders and asked that her last name not be used to protect her privacy, said the already available antidepressants weren’t keeping her symptoms at bay, and she frequently felt “one step away from the abyss.” When she first heard about ketamine, from a support group for people with depression and other mood disorders, she was hesitant.

“I kind of hemmed and hawed, because I’d heard that K was a street drug,” Mary said. “But then I said, ‘What do I have to lose?’ So I went and did it.”

The results were quick: Within four days, “the cloud had lifted,” she said. More than a year later, she is still feeling good with regular infusions every three or four weeks. During the ketamine infusion, Mary said she’ll feel the dissociation, which she described as feeling like she’s viewing the world around her as though it were a movie and not her own life.

She said she’s pleased the FDA approved Spravato, though she hasn’t decided whether she’ll switch from the IV ketamine to the nasal spray. She hopes that the FDA approval will give some validation to ketamine and encourage others to try it.

Mary gets her infusions at Palo Alto Mind Body, where Dr. M Rameen Ghorieshi started offering ketamine two years ago. He’s certified with the maker of Spravato — Janssen Pharmaceuticals, a branch of Johnson and Johnson — to provide the drug, though he doesn’t know when he’ll actually start giving the nasal spray to patients.

Ghorieshi said that although he’s been offering IV ketamine for more than two years, he shares his colleagues’ wariness of the long-term effects of regular use of the drug. He hopes FDA approval will encourage further research.

“At this point we’ve done 1,000 infusions. The outcomes have exceeded my own expectations,” Ghorieshi said. “But anecdotes are not clinical trials. I approach this very cautiously. What I don’t want is 20 or 30 years from now to look back and say, ‘What did we do?’”



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