Opiates are essential for treating pain, but termination of
opiate therapy can cause a debilitating withdrawal syndrome
in chronic users. To alleviate or avoid the aversive symptoms
of withdrawal, many of these individuals continue to use
opiates1–4. Withdrawal is therefore a key determinant of opiate
use in dependent individuals, yet its underlying mechanisms
are poorly understood and effective therapies are lacking. Here,
we identify the pannexin-1 (Panx1) channel as a therapeutic
target in opiate withdrawal. We show that withdrawal from
morphine induces long-term synaptic facilitation in lamina I
and II neurons within the rodent spinal dorsal horn, a principal
site of action for opiate analgesia. Genetic ablation of Panx1
in microglia abolished the spinal synaptic facilitation and
ameliorated the sequelae of morphine withdrawal. Panx1
is unique in its permeability to molecules up to 1 kDa in size
and its release of ATP5,6. We show that Panx1 activation
drives ATP release from microglia during morphine withdrawal
and that degrading endogenous spinal ATP by administering
apyrase produces a reduction in withdrawal behaviors.
Conversely, we found that pharmacological inhibition of
ATP breakdown exacerbates withdrawal. Treatment with
a Panx1-blocking peptide (10panx) or the clinically used
broad-spectrum Panx1 blockers, mefloquine or probenecid,
suppressed ATP release and reduced withdrawal severity.
Our results demonstrate that Panx1-mediated ATP release
from microglia is required for morphine withdrawal in rodents
and that blocking Panx1 alleviates the severity of withdrawal
without affecting opiate analgesia.
Even though millions of Americans are in the midst of this battle, few medications are available to effectively manage their symptoms. This unavailability – and the onset of painful withdrawal symptoms – are often enough to make many people give up and return to opioids for relief.
But this could soon change…
According to the results of a recent study, help for intense withdrawal symptoms might be on the horizon, thanks to the discovery of a new drug.
“Opioid withdrawal is aversive, debilitating, and can compel individuals to continue using the drug in order to prevent these symptoms,” explains lead researcher Tuan Trang, PhD.
“In our study, we effectively alleviated withdrawal symptoms in rodents, which could have important implications for patients that may wish to decrease or stop their use of these medications.”
Researchers from the University of Calgary’s Faculty of Veterinary Medicine and Hotchkiss Brain Institute investigated the process of withdrawal and its’ possible causes. The study involved rats which had been given two potent opioids, morphine and fentanyl. The team identified the glycoprotein, pannexin-1, as the source of withdrawal symptoms in rodents. Pannexin-1 is also located throughout the human body, including the brain and spinal cord.
After identifying the cause of these symptoms, the team tested a drug already proven to block the effects of pannexin-1 called, Probenecid. It’s an anti-gout medication that’s fairly cheap and has few side effects.
The results showed this medicine was “effective in reducing the severity of withdrawal symptoms in opioid-dependent rodents.” Another encouraging aspect about their findings: the medication didn’t affect an opioids’ ability to relieve pain.
Previous research hadn’t explored this avenue, and this investigation has provided a better understanding of opioid withdrawal at the cellular level.
Canadian pain researcher, Dr. Michael Salter, notes, “This is an exciting study which reveals a new mechanism and a potential therapeutic target for managing opioid withdrawal. The findings of Dr. Trang and his team could have important implications for people on opioid therapy and those attempting to stop opioid use.”
The team behind the study plan to continue their work and hope this new insight will lead to the creation of a more effective treatment method for the symptoms of withdrawal. Dr. Trang says their next steps will be to determine the drug effectiveness in humans and to ensure its’ safety. Their goal is to develop an effective method to treat the millions struggling with pain management and opioid dependency across the nation and around the world.
These results have already lead to the development of a clinical trial at the Calgary Pain Clinic.
The National Institute on Drug Abuse (NIDA), part of the National Institutes of Health, is pleased to announce that lofexidine, the first medication for use in reducing symptoms associated with opioid withdrawal in adults, has been approved by the U.S. Food and Drug Administration. Lofexidine, an oral tablet, is designed to manage the symptoms patients often experience during opioid discontinuation. Opioid withdrawal symptoms, which can begin as early as a few hours after the drug was last taken, may include aches and pains, muscle spasms/twitching, stomach cramps, muscular tension, heart pounding, insomnia/problems sleeping, feelings of coldness, runny eyes, yawning, and feeling sick, among others. The product will be marketed under the brand name LUCEMYRATM.
In 2016, more than 42,000 people died from an opioid overdose, or approximately 115 people per day. Although effective treatments exist for opioid addiction, painful and difficult withdrawal is one of the reasons treatment fails, and relapse occurs. By alleviating symptoms associated with opioid withdrawal, LUCEMYRA could help patients complete their discontinuation of opioids and facilitate successful treatment. To date, no other medications have been approved to treat opioid withdrawal symptoms.
LUCEMYRA will be marketed by US WorldMeds, a specialty pharmaceutical company that acquired a license for lofexidine from Britannia Pharmaceuticals in 2003. NIDA provided funding to US WorldMeds to support clinical trials to document the clinical pharmacokinetics of lofexidine and to test medical safety and efficacy of the medication, as compared to a placebo, among patients undergoing medically supervised opioid discontinuation. LUCEMYRA is expected to be commercially available in the United States in August 2018.
In 2016, 115 Americans died every day from an overdose involving prescription or illicit opioids. Addiction to any drug has multiple components—altered functioning of the reward system, learned associations with drug cues that promote preoccupation and craving, and changes to prefrontal circuits necessary for proper exertion of self-control. But physiological and psychological withdrawal symptoms play a major role in driving users repeatedly back to the drug, despite efforts to stop using.
Withdrawal is notoriously hard to endure for people addicted to opioids. Physical symptoms can start a few hours after last taking the drug and may include stomach cramps, aches and pains, coldness, muscle spasms or tension, pounding heart, insomnia, and many others. These symptoms, along with mood changes, like depression and anxiety, are a major reason people with opioid addiction may relapse. Yet until now, no medication has been approved to treat withdrawal.
This week, the Food and Drug Administration (FDA) approved lofexidine, the first medication targeted specifically to treat the physical symptoms associated with opioid withdrawal. NIDA’s medications development program helped fund the science leading to the drug’s approval. Lofexidine could benefit the thousands of Americans seeking medical help for their opioid addiction, by helping them stick to their detoxification or treatment regimens.
Two of the three FDA-approved medications to treat opioid use disorder, methadone and buprenorphine, can be initiated while a person is experiencing withdrawal symptoms, and can help curb craving. However, these medications are not always easy to access, and at this point are only received by a minority of people with opioid use disorder. The third FDA-approved drug, extended-release naltrexone, has also been found effective, but only after people have been fully detoxified. The need to detox first—and endure those symptoms—prevents many patients from being treated with naltrexone. Lofexidine could make a big difference in making the latter treatment option more widely used.
Lofexidine is not an opioid. It acts to inhibit the release of norepinephrine in the brain and elsewhere in the nervous system. It was originally developed as a medication for hypertension, but has mainly been used for opioid withdrawal in the United Kingdom since the early 1990s. US WorldMeds acquired a license for lofexidine from Britannia Pharmaceuticals in 2003 and will market it in the US under the brand name LUCEMYRATM beginning this summer. NIDA helped fund the clinical trials to test lofexidine’s pharmacological properties, safety, and efficacy in patients who were discontinuing opioid use under medical supervision.
Lofexidine cannot address the psychological symptoms of opioid withdrawal; further research is needed to develop medications that could address mood problems during detoxification and after. But approval of the first medication to treat the physical symptoms of opioid withdrawal is a major milestone, one that could improve the lives and treatment success of thousands of people living with opioid addiction. And by helping prevent relapse, it could save lives. The approval of lofexidine is also a welcome example of the power of public-private collaborations in developing new treatments.
MIAMI — Lofexidine (Lucemyra, US Worldmeds), which has been in use in the United Kingdom for more than 20 years, is now
available in the United States. The drug is used in the management of symptoms of severe opioid withdrawal.
Dr Danesh Alam
In a double-blind, placebo-controlled, multicenter trial in opioid-dependent patients, lofexidine significantly improved opioid
withdrawal symptoms and significantly increased completion of a 7-day opioid discontinuation treatment program compared with
“We desperately need something to address the opioid crisis, where we are losing about 100 Americans every day, with some
16 million on opioids,” Danesh Alam, MD, Northwestern Medicine Central Dupage Hospital, Winfield, Illinois, told Medscape
“Now we have a drug that actually enables us to achieve a rapid withdrawal from opioids. When we use lofexidine, we can
literally bring in someone using opioids, give them this drug, and they can immediately stop using opioids,” said Alam.
The study was presented at the American Society for Clinical Psychopharmacology (ASCP) 2018.
A Better Alternative
Currently, the standard of care for the treatment of opioid withdrawl is medication-assisted therapy with buprenorphine (multiple
brands), but many patients wish to stop using opioids completely, Alam said.
“Buprenorphine is essentially another opioid, albeit a designer opioid, but a number of patients object to clinicians saying that
the best evidence is to switch them over to buprenorphine and do buprenorphine for the rest of their life,” he said.
Lofexidine, a selective alpha-2-adrenergic agonist, acts on the central nervous system. Through its effect on the brain stem, it
reduces the symptoms of withdrawal to a point at which they become very tolerable.
“We found in our study that you could basically give patients the lofexidine and stop the opiate. In the majority of cases, the
withdrawal symptoms at that point were mild,” Alam said.
The researchers enrolled 602 men and women aged 18 years or older who sought treatment for dependence on short-acting
opioids. Most were men (71%); the mean age of the patients was 35 years (±11 years).
Most patients (83%) were dependent on heroin.
Participants were randomly assigned to receive placebo, lofexidine 0.6 mg qid (2.4 mg/day), or lofexidine 0.8 mg qid (3.2
mg/day) for 7 days after abrupt opioid discontinuation.
The study assessed the benefit of lofexidine with the Short Opiate Withdrawal Scale–Gossop (SOWS-G), a 10-item inventory of
common opioid withdrawal symptoms in which higher scores indicate worse symptoms; by the percentage of participants who
completed the study; and by use of the Clinical Opiate Withdrawal Scale (COWS), an 11-item inventory of opioid withdrawal
signs and symptoms in which higher scores indicate worse symptoms.
Scores on the SOWS-G were lower for patients treated with lofexidine at both doses compared to patients given placebo (-0.21
for lofexidine 2.4 mg, P = .02; and -0.26 for lofexidine 3.2 mg, P = .003). More patients in the lofexidine-treated group completed
the 7-day trial than in the placebo group (41.5% in the 2.4-mg group (odds ratio [OR], 1.85, P = .007), and 39.6% in the 3.2-mg
group (OR, 1.71; P = .02), vs 27.8% for placebo.
Mean COWS scores were significantly lower on days 1 to 5 for patients in the lofexidine groups than for patients who received
placebo (P < .01).
The most common side effects seen with lofexidine were hypotension, orthostatic hypotension, and bradycardia, but they
resulted in few study discontinuations.
The US debut of lofexidine comes at a crucial time. It was recently granted approval by the US Food and Drug Administration
(FDA), as reported by Medscape Medical News.
This approval came after 17 years of hard work on the part of the National Institute on Drug Abuse (NIDA).
Ketamine has been around for a long time and offers successful opportunities to treat individuals with very resistant depression, PTSD and anxiety. It is also rapid acting. Look at the following links below,
Useful in depression,anxiety, Bipolar, PTSD, pain, migraines, Bipolar, post partum depression, fibromyalgia, and multiple other hard-to-treat disorders. Here are some links and information below to popular press articles on Ketamine!
Chris Stephens, 28, has been battling depression all of his life. At times he wouldn’t get out of bed for weeks. In January, he said his depression hadn’t returned since he started taking ketamine.
Lianne Milton/For NPR
Scientists say they have figured out how an experimental drug called ketamine is able to relieve major depression in hours instead of weeks.
Researchers from Yale and the National Institute of Mental Health say ketamine seems to cause a burst of new connections to form between nerve cells in parts of the brain involved in emotion and mood.
The discovery, described in Science, should speed development of the first truly new depression drugs since the 1970s, the researchers say.
“It’s exciting,” says Ron Duman, a a psychiatarist and neurobiologist at Yale University. “The hope is that this new information about ketamine is really going to provide a whole array of new targets that can be developed that ultimately provide a much better way of treating depression.”
Ketamine is an FDA-approved anesthetic. It’s also a popular club drug that can produce out-of-body experiences. Not exactly the resume you’d expect for a depression drug.
But a few years ago, researchers discovered that ketamine could help people with major depression who hadn’t responded to other treatments. What’s more, the relief came almost instantly.
The discovery “represents maybe one of the biggest findings in the field over the last 50 years,” Duman says.
A rat neuron before (top) and after (bottom) ketamine treatment. The increased number of orange nodes are restored connections in the rat’s brain.
Ronald Duman/Yale University
Depression is associated with a loss of so-called synaptic connections between nerve cells, Duman says. So he and other scientists began to study mice exposed to stresses that produce symptoms a lot like those of human depression.
The stressed mice lost connections in certain parts of the brain. But a dose of ketamine was able to “rapidly increase these connections and also to rapidly reverse the deficits that are caused by stress,” Duman says.
A team at the National Institute of Mental Health also has found evidence that ketamine works by encouraging synaptic connections.
It’s possible to see the change just by studying rodent brain cells with a microscope, says Carlos Zarate from the Mood and Anxiety Disorders Program at NIMH.
A healthy neuron looks like a tree in spring, he says, with lots of branches and leaves extending toward synaptic connections with other neurons. “What happens in depression is there’s a shriveling of these branches and these leaves and It looks like a tree in winter. And a drug like ketamine does make the tree look like one back in spring.”
And there’s also indirect evidence that ketamine is restoring synaptic connections in people, Zarate says.
His team studied 30 depressed patients who got ketamine. And they found changes in brainwave activity that indicated the drug had strengthened connections between neurons in areas of the brain involved in depression.
All of this research is intended to produce drugs that will work like ketamine, but without the hallucinations. And several of these alternative drugs are already being tried in people.
Preliminary results suggest that “some of these compounds do have rapid antidepressant effects without the side effects that occur with ketamine,” Zarate says.
One of these drugs, called GLYX-13, has already been tested in two large groups of people — a key step toward FDA approval. The company that makes the drug, Naurex, says it will tell scientists how well GLYX-13 works at a meeting in December.
Fear of Harm (FOH) is a pediatric onset phenotype of bipolar disorder (BD) characterized by BD plus treatment resistance, separation anxiety, aggressive obsessions, parasomnias, and thermal dysregulation. Intranasal ketamine (InK) in 12 youths with BD-FOH produced marked improvement during a two-week trial. Here we report on the open effectiveness and safety of InK in maintenance treatment of BD-FOH from the private practice of one author.
As part of a chart review, patients 18 years or older and parents of younger children responded to a clinical effectiveness and safety survey. Effectiveness was assessed from analysis of responses to 49 questions on symptomatology plus qualitative content analyses of written reports and chart review. Adverse events (AEs) were analyzed by frequency, duration and severity. Peak InK doses ranged from 20 to 360mg per administration.
Surveys were completed on 45 patients treated with InK for 3 months to 6.5 years. Almost all patients were “much” to “very much” improved clinically and in ratings of social function and academic performance. Significant reductions were reported in all symptom categories. There were 13 reports of persistent AEs, none of which resulted in discontinuation. Acute emergence reactions were sporadically observed in up to 75%, but were mild and of brief duration.
Retrospective review from a single practice without placebo control with potential for response and recall bias.
InK every 3-4 days at sub-anesthetic doses appeared to be a beneficial and well-tolerated treatment. Use of InK may be considered as a tertiary alternative in treatment refractory cases. Randomized control trials are warranted.
Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system.
The effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD).
Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion.
Retrospective nature of this study, lack of control group and use of self-report depression ratings scales.
This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population.
Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system.
The effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD).
Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion.
Retrospective nature of this study, lack of control group and use of self-report depression ratings scales.
This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population.
This article looked at the adverse event reporting system, evaluating the ‘side effects’ of Ketamine, which demonstrated LOWER depression rates in patients using Ketamine for pain. These same patients had fewer side effects from those pain medicines as well when they used Ketamine. In numerous settings, we have utilized Ketamine as an adjunct to control pain when opioids have failed (i.e.morphine) with excellent results.
Depression affects 8-12 % of the population at any one time and steals away quality of life as well as productivity. Depression is listed as the 4th leading cause of disease burden on the population by the World Health Organization. Standard medications, such as SSRI antidepressants, may be ineffective or take several weeks to begin to have any effect. Ketamine has been shown to result in immediate (12-24 hours) improvement of depressive symptoms in a large percentage of patients. We see the same in many of our office infusions.
There is an inflammatory component to depression. This same article points out that Diclofenac, minocycline (an antibiotic), and Botox, also have some antidepressant effect as a result of their anti-inflammatory effects.
The bottom line is that Ketamine showed effectiveness for treatment-resistant depression in this article.
Has anyone had Botox with a Ketamine infusion? Just curious…
Current therapeutic approaches to depression fail for millions of patients due to lag in clinical response and non-adherence. Here we provide new support for the antidepressant effect of an anesthetic drug, ketamine, by Inverse-Frequency Analysis of eight million reports from the FDA Adverse Effect Reporting System. The results of the examination of population scale data revealed that patients who received ketamine had significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain. The analysis also revealed that patients who took ketamine had significantly lower frequency of reports of pain and opioid induced side effects, implying ketamine’s potential to act as a beneficial adjunct agent in pain management pharmacotherapy. Further, the Inverse-Frequency Analysis methodology provides robust statistical support for the antidepressant action of other currently approved therapeutics including diclofenac and minocycline.
The World Health Organization estimates depression as the 4th highest disease burden in the world1. In majority of the countries lifetime depression prevalence ranges 8–12%2,3,4. Current standard of practice of depression treatment consists of five main classes of antidepressants, serotonin reuptake inhibitors (SSRIs) being the most common. Nearly half of psychiatric and primary care patients discontinue their antidepressant therapy prematurely5. The main reasons for the discontinuation of therapy include late onset of beneficial outcomes, lack of efficacy for a fraction of patients, adverse reactions, fear of drug dependence, and lack of mechanisms to enforce adherence5. The initial therapeutic effect of antidepressants is delayed by 2–3 weeks after the first dose and the optimal effect is delayed by 6–10 weeks6. The long lag period renders the standard of care antidepressants ineffective for suicidal patients who can’t afford to wait 2–6 weeks. Aside from the lag in antidepressant effects, there is insufficient evidence that antidepressants prevent suicide during long-term treatment7, and in many cases the antidepressant increases the risk of suicidal thoughts and actions8. Efficacy is another issue affecting depression treatment. In the STAR*D protocol study depression remission is 67% after every drug class and drug class combination is tried9.
Because of these problems, some clinicians have been driven to utilize other drugs, such as ketamine, for treatment resistant depression (TRD) patients10,11,12. Ketamine is a drug used illicitly as a hallucinogen and clinically as an anesthetic since 1970’s. It is given intravenously, almost exclusively, due to a lack of an approved oral formulation. There have been some clinical trials where ketamine shows acute efficacy in treating TRD10,11, bipolar depression12 and major depressive disorder with suicidal ideation13, but the number of subjects in these trials ranges from 20 to 57 patients. There are financial and ethical obstacles for a larger scale clinical trial. Here we sought larger scale statistical evidence of ketamine antidepressant action in the FDA Adverse Event Reporting System (FAERS) postmarketing database containing over eight million patient records. Although FAERS was originally intended to track frequent adverse events, with sufficient amount of data, it can also be used to track the beneficial outcomes indirectly through monitoring reductions of related complaint frequencies. Here we apply Inverse-Frequency Analysis (IFA), which looks for statistically significant values of the negative log odds ratio (LogOR).
We found that patients listed in the FAERS database who received ketamine in addition to other therapeutics had significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain (LogOR −0.67 ± 0.034) (Fig. 1c). This reduction in depression is specific to ketamine and is known to be much more rapid than current antidepressants, making this observed effect very promising for treatment of patients with acute depressive or suicidal episodes11. These patients cannot afford to wait up to six weeks for reductions in their depressive symptoms. Pain reports were also significantly lower for ketamine patients (LogOR −0.41 ± 0.019) (Fig. 1c)
Legend: (a) Frequencies of adverse events in patients on FAERS who took ketamine. Adverse events above 2.5% were reported. (b) Odds ratios were calculated comparing adverse event rates of ketamine patients (n = 41,337) and pain patients (n = 238,516). (c) LogOR of pain and depression event rates were calculated from the ketamine and pain patient cohorts. Negative values showing protective effect of ketamine. (d) LogOR of constipation, vomiting, and nausea were calculated from the ketamine and pain patient cohorts. Negative values showing protective effect of ketamine.
The analysis of the whole FAERS database revealed several other unintentional depression reducing drugs among antibiotics, cosmeceuticals and NSAIDS (Fig. 2). Our data supported previous studies that observed the psychiatric polypharmacology of minocycline, a tetracycline antibiotic14 (Fig. 2). The NSAID, diclofenac, was also observed to have some antidepressant properties (Fig. 2). It is theorized that both of these drugs may accomplish antidepressant effects through an anti-inflammatory mechanism15. Because of the antidepressant activity of several NSAIDs, we further separated the non-ketamine pain cohort. Ketamine patients were then compared to patients who received any other combination of drugs for pain excluding NSAIDs. It was observed that depression event rates remained low (LogOR −0.56 ± 0.035) (Fig. 2).
LogOR of psychiatric events were calculated from FAERS patients who used botox, diclofenac or minocycline. FAERS patients who took any drugs for the indication of depression were used as the control cohort. Negative values showing protective effect
The reduction of depression rates in ketamine patient records makes a case for study of ketamine as a psychiatric drug. These results imply that ketamine may be further explored as a monotherapy or adjunct therapy for depression. It should also be noted that FAERS data revealed that ketamine use lead to renal side effects and awareness and caution in patients with renal or hepatic impairment may be warranted (Fig. 1a and b).
As an important side note, we also evaluated efficacy and side effects with the use of ketamine for pain management. We found that patients who were on ketamine had reduced opioid induced side effects including constipation (LogOR −0.17 ± 0.023), vomiting (LogOR −0.16 ± 0.025), and nausea (LogOR −0.45 ± 0.034) than patients who received any other combination of drugs for pain indications (Fig. 1d). Our data supports ketamine’s opioid-sparing properties and alludes to the fact that patients may receive benefits of improved pain, reduced requirement of opioids, and ultimately less opioid reduced side effects.
The results of this study support previous small scale studies’ conclusions that ketamine is a good monotherapy or adjunct therapy for depression. In clinical practice ketamine would be especially useful for depression because of the quick onset of its action compared to existing first line therapies10,11,12,13. Regardless of the causative mechanism ketamine appears to have therapeutic potential for TRD. Further, the potential to reduce many of the most complained side effects of opioid treatment makes ketamine adjunct therapy for pain seem desirable.
Overall, this study demonstrates that the therapeutic potential of ketamine can be derived from appropriate statistical analysis of existing population scale data. This study also outlines a methodology for discovering off label pharmacology of existing approved drugs. This method can be applied to other indications and may reveal new important uses of already approved drugs, providing reliable justification for new indications without large investments in additional clinical trials.
The rest of the article can be easily accessed from the above Link.
Call 703-844-0184 to schedule a Ketamine evaluation or infusion.
Before getting ketamine infusions for depression, you’ll likely want to know what a ketamine infusion experience is like. While the ketamine infusion experience is different from person to person, the protocol for ketamine infusions for depression is similar for everyone. Read on to learn what it’s really like to receive intravenous ketamine infusions.
What Is a Ketamine Infusion?
A ketamine infusion is a dose of ketamine that is given via the intravenous (IV) route of administration. Ketamine infusions are typically used to treat major depression or depression in bipolar disorder but can be used to treat chronic pain conditions as well.
Before Getting a Ketamine Infusion
Before getting a ketamine infusion, you should expect thorough medical and psychiatric evaluations as well as medical tests to make sure you are healthy enough for the treatment. These assessments and tests are very important as ketamine infusions can be challenging both mentally and physically and only a doctor who is well-acquainted with your health can make good decisions for you.
Ketamine Infusion Procedure
You will likely be shown to a room with a comfortable reclining chair or bed. You will not need to disrobe or wear a hospital gown for treatment. The Ketamine Advocacy Network suggests that you always request a single-person room as a ketamine infusion is a very personal experience. A loved one is usually allowed to stay with you during the ketamine infusion treatment if you want. You’ll then be connected to vital sign monitors such as pulse and oxygen saturation monitors.
It is at this point that you’ll have an IV inserted. A tiny needle is used to insert a tube into a vein in your hand or arm and many find this to be painless. The tube will be connected to a bag held a couple of feet above you. The bag contains the specific dose of ketamine you will require and it will be delivered directly into your bloodstream at a controlled rate. The rate may be adjusted during your treatment to maximize its benefit. It takes approximately 45 minutes for a ketamine infusion and you may need to be under observation after that for an hour or occasionally more. You cannot drive yourself home after an infusion.
People, typically, initially receive six infusions over the course of two-three weeks.
What Does Getting an IV Ketamine Infusion for Depression Feel Like?
Once the ketamine enters your system, it will reach your brain within seconds and you will quickly be able to feel its effects. You won’t be able to stand or converse normally and you’ll feel extremely relaxed but you will still be awake. While others may view a person that seems almost asleep, your brain will still fully be engaged. While this sensation is often found to be “weird”, most people do find it pleasant.
Experience of Side Effects of the Ketamine Infusion
During the infusion, you may experience dissociation, where the mind and body seem to separate. This side effect of the ketamine infusion can often be minimized simply by opening your eyes.
As stated, your mind will be very active during the IV infusion so it may wander to thoughts of trauma or anxiety, but unlike your usual feelings around those thoughts, you will view it matter-of-factly. One patient described his ketamine infusion experience like this:
“. . . you start disassociating with everything, like you’re observing, not participating in anything. It’s really weird . . . As far as the mind goes, you start going through these weird levels, kind of like in the movies Inception or The Matrix, where you don’t know what’s real.
“You start thinking about all kinds of stuff. Whatever races through your mind—and usually when you’re depressed it’s negative sh*t—when you’re on ketamine, it’s just like: ‘Well, nothing I can do about that.’ You feel like, ‘I’m not in control, and that’s fine; you’re going to die someday and that’s just life.’ You kind of learn to just accept it, I guess.”
Although most patients do experience relaxation during a ketamine infusion, there can be moments of fright, particularly if you go into the experience with very high anxiety. Listening to calming music or watching a calming image may help with this, however.
Feeling Better After the Ketamine Infusion Procedure
What’s important to remember is that no matter what you experience during a ketamine infusion, it’s the changes that the ketamine makes to your brain that relieve depression and not the infusion experience itself.
Ketamine is a relatively new treatment for depression so people are often looking for ketamine treatment for depression reviews to help guide their choices. This is understandable as ketamine treatment cost falls between $400-800 per intravenous (IV) infusion and more than six infusions may be needed. Read on for real patients’ ketamine for depression reviews.
Ketamine Treatment for Depression Reviews
It’s important to note that reviews for any type of treatment are personal and individual. This means that any one person may or may not have the same experience as you. This is why it’s important to work with your doctor to decide if ketamine is a good treatment option for your depression.
That being said, there are ketamine treatment for depression reviews available.
A site like PatientsLikeMe can be valuable as individual patients can report their experiences with a treatment. As of August 2017, four patients who took ketamine for major depressive disorder and two patients who took ketamine for bipolar depression have left reviews. Of the six, three indicated that ketamine had “major effectiveness” on their condition. Two patients noted moderate effectiveness and one noted no effectiveness. Side effects to ketamine included: dissociation, dizziness, nausea, memory problems, cognition problems and drowsiness. Two of the patients noted no side effects although one of those also reported no useful effect either.
When looking at these ketamine infusion reviews, most people were happy with the treatment, with one patient saying, “Very effective. I would do it again in a heartbeat.”
When looking at the reviews that all patients left, regardless as to the reason the ketamine was prescribed, two out of 24 noted severe side effects and nine out of 24 noted no side effects.
Ketamine Review Article
In 2015, Vice.com published a ketamine review article called, I Used Ketamine to Treat My Depression. In it, one person with bipolar depression discusses his experience with receiving ketamine infusion for depression. Brent Miles, a 41-year-old songwriter and journalist from Phoenix, Arizona, regularly got ketamine infusion treatments at a clinic in North Scottsdale in 2013 and shares his story.
Ketamine Treatment for Depression Reviews by Doctors
As with many treatments, some doctors are wary of this new depression treatment while others forge ahead with cautious optimism.
“A really important part of these recommendations is to make sure people fully understand what the risks and benefits are to treatment so that they are able to make an informed decision based on knowing what the risk-benefit ratio is,” said Gerard Sanacora, MD, PhD, professor of psychiatry and director of the Yale Depression Research Program.
Dr. Sanacora also added:
“The reality is that this is a unique situation where we have a tremendously promising treatment. We use it a lot, and I believe this really is a transformative change in the field, but we do have to appreciate the limits of the knowledge that we are working with right now.”
The side effects of ketamine for depression are typically mild but can range in severity. Understanding the ketamine infusion therapy for depression side effects before starting treatment is a good idea so that you know what to look for and aren’t surprised by the more common ketamine side effects.
Side Effects of Ketamine
It’s important to remember that the doses of ketamine for depression treatment are far smaller than any dose that would be used recreationally or as an anesthetic (Can You Get Addicted to Ketamine?). Thus, if you read about the side effects of ketamine in general, you will likely see more severe and different side effects listed than those experienced by those being treated for depression.
Some of the common side effects experienced when larger dosages are used include:
High blood pressure
Increased cardiac output
Pressure inside the skull (intracranial pressure)
Irregular heart rhythm
Seizure-type movements (tonic-clonic movements)
Side Effects of Ketamine for Depression
As mentioned, dosages of ketamine when used to treat depression are very small. However, ketamine infusion therapy side effects still exist.
According to a small 2012 study wherein patients received up to six ketamine infusion treatments for treatment-resistant depression, the following were the commonly-reported side effects:
The presence of psychotic symptoms (delusions and/or experiences of things that don’t exist such as hallucinations)
Dissociative symptoms (feeling “out of body,” disconnected, etc.)
Feeling “strange” or “unreal”
Feeling drowsy or sleepy
Elevated heart rate or blood pressure
Notably, only four people in the study (16.7%) reported any side effect that impaired functioning at any time.
That said, the majority of people who were given ketamine infusion therapy for depression did experience some side effects, most remitting within two hours after the infusion.
Those who responded positively to the ketamine treatment experienced the same level and type of side effects that those who did not respond experienced.
Positive Effects of Ketamine for Depression
In a small, recent study, it was found that within two hours of the first dose of ketamine, each individual item on a depression scale known as the Montgomery– Asberg Depression Rating Scale (MADRS), was reduced with the exception of appetite and sleep items which couldn’t be assessed at that time.
The following positive effects of ketamine for depression were seen as reductions in:
Inability to feel
Feelings of weariness, diminished energy or listlessness (lassitude)
The largest positive changes were seen in lassitude, concentration difficulties, and apparent sadness.
It’s important to remember that while these positive ketamine health effects will be seen by many, not everyone responds to ketamine treatment in this way. In the above-mentioned study, 71% of people had a positive response to ketamine treatment for depression and it is known that those receiving more treatments have a better chance at a positive response.
Ketamine isn’t just a drug used to treat depression, chronic pain or as an anesthesia, ketamine is also a street drug of abuse. Often called “special k,” ketamine is used in large doses by some in the party scene. It’s important to remember, however, that recreationally, people take much larger doses of ketamine than are used in depression treatment (How Does Ketamine Work for Depression?). This means that recreational users are more likely to experience increasing tolerance to the drug’s effects, seek greater doses and become addicted.
Ketamine is the number one drug of abuse in Asia, particularly Hong Kong. Some of the ketamine found on the street is diverted from pharmaceutical supplies but there is also increasing evidence of ketamine production specifically for street use, particularly in India and China. Ketamine may also be found in ecstasy in Asia.
Ketamine is also a drug of abuse in the United States. The reason why people abuse ketamine is its desirable acute effects on the person. If a person takes a street dose of ketamine, he or she may experience:
Reduced sensations in the body / a lack of pain
A floating or detached feeling
A feeling of being incapable of moving
A change in how the person sees and hears things, possibly causing hallucinations
Some people find these effects desirable. However, ketamine can also cause:
Impairment in short- and long-term memory impairment
Difficulty in cognition
Impaired reaction time
Death from acute ketamine use is rare but does occur.
If a person continues to abuse ketamine, over time even worse effects can be felt. Someone who is addicted to ketamine or who consistently abuses ketamine may experience:
Very serious bladder problems possibly leading to the bladder needing removal
Serious damage to the urinary tract
Impaired gallbladder activity
Extreme pain, particularly during urination
You may not experience a physical addiction to ketamine but you can become addicted to ketamine psychologically. Being addicted to ketamine is no joke and anyone who abuses ketamine or who is addicted to ketamine needs to seek help immediately.
How to Get Off Ketamine
Getting off ketamine involves the same thing as getting off of other drugs: going through withdrawal. Withdrawal effects make it difficult for someone trying to get off ketamine to stay sober, but withdrawal effects can be managed.
If you’re trying to get off of ketamine, symptoms of withdrawal that you might experience include:
Increased heart beat
Loss of motor skills
Loss of coordination
These effects are not typically medically dangerous although if they get out of hand, medical intervention may be needed in the short-term. While these withdrawal effects may sound awful, it’s important to remember that these effects are short-lived and day-by-day, you will start to feel better.
I attached a youtube video on SAD – seasonal Affective Disorder
Ketamine, notorious club drug, shows promise as a treatment for depression, studies indicate
April 20, 2018 by John Keilman, Chicago Tribune
Sabrina Misra suffered from depression for most of her life, but last summer, it became almost too heavy to bear.
Despite years of therapy and many medications, Misra, 36, had become so despondent that she started planning her suicide. But then her psychiatrist introduced her to a new treatment with an unusual back story.
The treatment was ketamine, an anesthetic used to sedate both people and animals before surgery. It’s also a notorious street drug, abused by clubgoers seeking a trancelike, hallucinatory high.
But in recent years, numerous studies have found that ketamine can be an effective and speedy treatment for people with depression—particularly those who, like Misra, have found little relief from other medications.
“After the first couple of treatments it didn’t seem to work, but after I hit my fourth one, everything started to change,” said Misra, a therapist and college instructor who lives in Lisle, Ill. “I went from actively wanting to kill myself to being fine.”
Though some researchers have found that ketamine can be a valuable antidepressant, no one has performed the large-scale clinical trials necessary to get U.S. Food and Drug Administration approval to use it a psychiatric medication.
Consequently, most insurance plans won’t pay for it, leaving patients to pay thousands of dollars out of pocket for a series of intravenous infusions.
Some warn that questions remain about ketamine’s long-term safety and effectiveness. Dr. James Murrough, a psychiatrist at the Icahn School of Medicine at Mount Sinai in New York, said people who misuse the drug have developed cognitive problems, and high doses have proved toxic in rats.
And because ketamine has a history of abuse, he said, doctors and patients must consider the threat of addiction.
“We think the risk is low, but it’s probably not zero, particularly if it gets scaled up,” he said. “There’s excitement but also a justified caution.”
Nonetheless, demand for the drug is so great that dozens of specialty clinics are popping up around the country. The doctors who run them say ketamine has helped most of their patients.
“It’s much better than anything we’ve had before,” said Dr. Abid Nazeer, the psychiatrist who treated Misra at his Oak Brook clinic, Advanced Psychiatric Solutions. “I’ve seen it work so quickly that one infusion gets rid of suicidal thoughts that had been there for 20 years.”
Ketamine was created as an anesthetic, and doctors including veterinarians and battlefield medics embraced it for its fast-acting properties and relative safety. But because it produces strong out-of-body sensations in high doses, it became a club drug, potent enough to send hundreds of people to emergency rooms each year.
In the 1990s, researchers discovered another use for ketamine: A small dose, they found, limits the concentration of a neurotransmitter called glutamate in the brain, and with startling speed, lifts the mood of many depression sufferers who haven’t been helped by medications like Prozac or Lexapro.
“Our standard antidepressants can take six to eight weeks to be effective—ketamine can take just one hour,” said Dr. Carlos Zarate of the National Institute of Mental Health, whose studies in the 2000s accelerated interest in the drug.
Over the past few years, doctors have opened specialty clinics that offer ketamine to patients who have depression or, to a lesser extent, chronic pain. Though the FDA has not approved those uses, the agency allows doctors to dispense drugs for “off-label” purposes if they believe it is medically appropriate.
The basic regimen calls for the intravenous infusion of a small dose—0.5 mg per kilogram of body weight, far less than someone would use to get high—six times over two weeks. After that, patients return every few weeks or months for booster doses.
Clinic operators say they screen clients to focus on those who have not improved with standard antidepressants.
“This is a last resort for those that are treatment-resistant,” said Dr. June Lee of Lombard’s Optimum Ketamine Center. “Most of the patients we’ve seen here have tried everything.”
Zarate said research has shown ketamine to be effective for about 60 percent of people with treatment-resistant depression, though some local clinics say their results have been better.
“We’ve had about a 70 percent response rate, but it really works for them,” said Dr. Vikas Patel, an emergency room physician who runs the Midwest Ketamine Center in Arlington Heights. “For the 30 percent it doesn’t work for, there’s no benefit at all. I would say there isn’t a big in-between.”
He charges $500 per infusion. Insurance typically won’t cover ketamine treatments, though Patel said he expects that to change. A pharmaceutical company is seeking FDA approval for a nasal spray, he said, and other companies are testing their own versions.
But for now, the out-of-pocket cost limits the number of people who can afford the treatment. Misra said that while she put the infusions on her credit card, seeing them as a life-or-death investment, others aren’t so fortunate.
“I have patients who are struggling right now, and they actually can’t swing it,” she said. “I think that’s a horrible thing. No one should have to die because they can’t pay for treatment.”
Dominic Sisti, who directs the Scattergood Program for Applied Ethics of Behavioral Health Care at the University of Pennsylvania, co-wrote a paper three years ago warning about the possible risks of using ketaminefor depression.
The research that has come out since then has persuaded him that it is appropriate for many people, he said, but he still believes doctors should share data on their results to further knowledge of the drug and improve the protocols for using it.
“In a sense, each patient they treat is an experiment of one,” he said. “It would be really helpful if all these clinics got together and figured out a way to report those outcomes. Without those data, I worry that someone’s going to get hurt.”
Antidepressant response within hours? Experts weigh evidence on ketamine as fast-acting treatment for depression
Recent studies suggest that ketamine, a widely used anesthetic agent, could offer a wholly new approach to treating severe depression—producing an antidepressant response in hours rather than weeks. Two reviews of recent evidence on ketamine and related drugs for treating depression appear in the Harvard Review of Psychiatry.
Ketamine and related drugs may represent a “paradigm shift” in the treatment of major depressive disorder (MDD) and bipolar depression—especially in patients who do not respond to other treatments, according to a review by Carlos A. Zarate, Jr, MD and colleagues at the National Institute of Mental Health. A second article explores evidence on the mechanisms behind ketamine‘s rapid antidepressant effects.
Growing Evidence, Clinical Caution about Ketamine for Severe Depression
Current treatments for MDD and bipolar depression have major limitations. Many patients with severe depressive symptoms don’t respond to available antidepressant drugs. Even for those who do respond, it may take several weeks before symptoms improve.
Ketamine, an anesthetic, is one of several glutamatergic drugs affecting neurotransmitters in the central nervous system. Over the past decade, several studies have reported “rapid, robust, and relatively sustained antidepressant response” to ketamine, injected intravenously at low, subanesthetic doses.
Dr. Zarate and colleagues review the research on ketamine and other glutamatergic drugs for depression. Ketamine, by far the best-studied of these medications, is notable for its very rapid antidepressant effects. In patients with treatment-resistant MDD, ketamine has produced initial reductions in depressive symptoms within two hours, with peak effects at 24 hours.
Ketamine may also rapidly reduce suicidal thoughts. Combined with other medications, ketamine has also produced rapid antidepressant effects in patients with treatment-resistant bipolar depression.
Prompted by these studies, some doctors are already using ketamine in patients with severe or treatment-resistant depression. However, since it is FDA-approved only as an anesthetic, use of ketamine in depressive disorders is “off-label,” unregulated, and not standardized. Many questions remain about its short- and long-term side effects and potential for abuse.
“Efforts are underway to bring ketamine to market, standardize its use, and determine its real-world effectiveness,” Dr. Zarate and coauthors write. They also present evidence on several other glutamatergic drugs. One drug, esketamine, has been given “breakthrough therapy” status by the FDA for patients at imminent risk of suicide.
Cristina Cusin, MD of Massachusetts General Hospital and colleagues review neuroimaging studies evaluating ketamine’s effects in the brain. The studies show ketamine-induced changes in several brain areas involved in the development of depression. Ketamine may exert its antidepressant effects by “acutely disabl[ing] the emotional resources required to perpetuate the symptoms of depression,” as well as by increasing emotional blunting and increasing activity in reward processing.
Independent of how ketamine works or its ultimate role in clinical treatment, antidepressant response to glutamatergic drugs points to an exciting conclusion: “that rapid antidepressant effects are indeed achievable in humans,” Dr. Zarate and coauthors write. “This paradigm shift lends additional urgency to the development of novel treatments for MDD and bipolar depression, particularly for patient subgroups that do not respond to currently available therapies.”
Ketamine was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients, according to researchers at Columbia University Medical Center (CUMC). They also found that ketamine’s anti-suicidal effects occurred within hours after its administration.
The findings were published online last week in the American Journal of Psychiatry.
According to the Centers for Disease Control and Prevention, suicide rates in the U.S. increased by 26.5 percent between 1999 and 2015.
“There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm,” said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. “Currently available antidepressants can be effective in reducing suicidal thoughts in patientswith depression, but they can take weeks to have an effect. Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients.”
Most antidepressant trials have excluded patients with suicidal thoughts and behavior, limiting data on the effectiveness of antidepressants in this population. However, previous studies have shown that low doses of ketamine, an anesthetic drug, causes a rapid reduction in depression symptoms and may be accompanied by a decrease in suicidal thoughts.
The 80 depressed adults with clinically significant suicidal thoughts who enrolled in this study were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.
Those in the ketamine group also had greater improvement in overall mood, depression, and fatigue compared with the midazolam group. Ketamine’s effect on depression accounted for approximately one-third of its effect on suicidal thoughts, suggesting the treatment has a specific anti-suicidal effect.
Side effects, mainly dissociation (feeling spacey) and an increase in blood pressure during the infusion, were mild to moderate and typically resolved within minutes to hours after receiving ketamine.
“This study shows that ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression,” said Dr. Grunebaum. “Additional research to evaluate ketamine‘s antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster acting and have the potential to help individuals who do not respond to currently available treatments.”
The study is titled, “Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial.”
Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients
Repeat intravenous treatment with low doses of the anesthetic drug ketamine quickly reduced suicidal thoughts in a small group of patients with treatment-resistant depression. In their report receiving Online First publication in the Journal of Clinical Psychiatry, a team of Massachusetts General Hospital (MGH) investigators report the results of their study in depressed outpatients who had been experiencing suicidal thought for three months or longer.
“Our finding that low doses of ketamine, when added on to current antidepressant medications, quickly decreased suicidal thinking in depressed patients is critically important because we don’t have many safe, effective, and easily available treatments for these patients,” says Dawn Ionescu, MD, of the Depression Clinical and Research Program in the MGH Department of Psychiatry, lead and corresponding author of the paper. “While several previous studies have shown that ketamine quickly decreases symptoms of depression in patients with treatment-resistant depression, many of them excluded patients with current suicidal thinking.”
It is well known that having suicidal thoughts increases the risk that patients will attempt suicide, and the risk for suicide attempts is 20 times higher in patients with depression than the general population. The medications currently used to treat patients with suicidal thinking—including lithium and clozapine—can have serious side effects, requiring careful monitoring of blood levels; and while electroconvulsive therapy also can reduce suicidal thinking, its availability is limited and it can have significant side effects, including memory loss.
Primarily used as a general anesthetic, ketamine has been shown in several studies to provide rapid relief of symptoms of depression. In addition to excluding patients who reported current suicidal thinking, many of those studies involved only a single ketamine dose. The current study was designed not only to examine the antidepressant and antisuicidal effects of repeat, low-dose ketamine infusions in depressed outpatients with suicidal thinking that persisted in spite of antidepressant treatment, but also to examine the safety of increased ketamine dosage.
The study enrolled 14 patients with moderate to severe treatment-resistant depression who had suicidal thoughts for three months or longer. After meeting with the research team three times to insure that they met study criteria and were receiving stable antidepressant treatment, participants received two weekly ketamine infusions over a three-week period. The initial dosage administered was 0.5 mg/kg over a 45 minute period—about five times less than a typical anesthetic dose—and after the first three doses, it was increased to 0.75 mg/kg. During the three-month follow-up phase after the ketamine infusions, participants were assessed every other week.
The same assessment tools were used at each visit before, during and after the active treatment phase. At the treatment visits they were administered about 4 hours after the infusions were completed. The assessments included validated measures of suicidal thinking, in which patients were directly asked to rank whether they had specific suicide-related thoughts, their frequency and intensity.
While only 12 of the 14 enrolled participants completed all treatment visits—one dropped out because of ketamine side effects and one had a scheduling conflict—most of them experienced a decrease in suicidal thinking, and seven achieved complete remission of suicidal thoughts at the end of the treatment period. Of those seven participants, two maintained remission from both suicidal thinking and depression symptoms throughout the follow-up period. While there were no serious adverse events at either dose and no major differences in side effects between the two dosage levels, additional studies in larger groups of patients are required before any conclusions can be drawn.
“In order to qualify for this study, patients had to have suicidal thinking for at least three months, along with persistent depression, so the fact that they experienced any reduction in suicidal thinking, let alone remission, is very exciting,” says Ionescu, who is an instructor in Psychiatry at Harvard Medical School. “We only studied intravenous ketamine, but this result opens the possibility for studying oral and intranasal doses, which may ease administration for patients in suicidal crises.”
She adds, “One main limitation of our study was that all participants knew they were receiving ketamine. We are now finishing up a placebo-controlled study that we hope to have results for soon. Looking towards the future, studies that aim to understand the mechanism by which ketamine and its metabolites work for people with suicidal thinking and depression may help us discover areas of the brain to target with new, even better therapeutic drugs.”
Dawn F. Ionescu et al, Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine, The Journal of Clinical Psychiatry (2016). DOI: 10.4088/JCP.15m10056
Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine: Secondary Analysis of an Open-Label Study
Background: Ketamine rapidly reduces thoughts of suicide in patients with treatment-resistant depression who are at low risk for suicide. However, the extent to which ketamine reduces thoughts of suicide in depressed patients with current suicidal ideation remains unknown.
Methods: Between April 2012 and October 2013, 14 outpatients with DSM-IV–diagnosed major depressive disorder were recruited for the presence of current, stable (≥3 months) suicidal thoughts. They received open-label ketamine infusions over 3 weeks (0.5 mg/kg over 45 minutes for the first 3 infusions; 0.75 mg/kg over 45 minutes for the last 3). In this secondary analysis, the primary outcome measures of suicidal ideation (Columbia-Suicide Severity Rating Scale [C-SSRS] and the Suicide Item of the 28-item Hamilton Depression Rating Scale [HDRS28-SI]) were assessed at 240 minutes postinfusion and for 3 months thereafter in a naturalistic follow-up.
Results: Over the course of the infusions (acute treatment phase), 7 of 14 patients (50%) showed remission of suicidal ideation on the C-SSRS Ideation scale (even among patients whose depression did not remit). There was a significant linear decrease in this score over time (P<.001), which approached significance even after controlling for severity of 6-item Hamilton Depression Rating Scale (HDRS6) core depression items (P=.05). Similarly, there were significant decreases in the C-SSRS Intensity (P<.01) and HDRS28-SI (P<.001) scores during the acute treatment phase. Two of the 7 patients who achieved remission during the acute treatment phase (29%) maintained their remission throughout a 3-month naturalistic follow-up.
Conclusions: In this preliminary study, repeated doses of open-label ketamine rapidly and robustly decreased suicidal ideation in pharmacologically treated outpatients with treatment-resistant depression with stable suicidal thoughts; this decrease was maintained for at least 3 months following the final ketamine infusion in 2 patients.
Ketamine improved bipolar depression within minutes
Bipolar disorder is a serious and debilitating condition where individuals experience severe swings in mood between mania and depression. The episodes of low or elevated mood can last days or months, and the risk of suicide is high.
Antidepressants are commonly prescribed to treat or prevent the depressive episodes, but they are not universally effective. Many patients still continue to experience periods of depression even while being treated, and many patients must try several different types of antidepressants before finding one that works for them. In addition, it may take several weeks of treatment before a patient begins to feel relief from the drug’s effects.
For these reasons, better treatments for depression are desperately needed. A new study in Biological Psychiatry this week confirms that scientists may have found one in a drug called ketamine.
A group of researchers at the National Institute of Mental Health, led by Dr. Carlos Zarate, previously found that a single dose of ketamine produced rapid antidepressant effects in depressed patients with bipolar disorder. They have now replicated that finding in an independent group of depressed patients, also with bipolar disorder. Replication is an important component of the scientific method, as it helps ensure that the initial finding wasn’t accidental and can be repeated.
In this new study, they administered a single dose of ketamine and a single dose of placebo to a group of patients on two different days, two weeks apart. The patients were then carefully monitored and repeatedly completed ratings to ‘score’ their depressive symptoms and suicidal thoughts.
When the patients received ketamine, their depression symptoms significantly improved within 40 minutes, and remained improved over 3 days. Overall, 79% of the patients improved with ketamine, but 0% reported improvement when they received placebo.
Importantly, and for the first time in a group of patients with bipolar depression, they also found that ketamine significantly reduced suicidal thoughts. These antisuicidal effects also occurred within one hour. Considering that bipolar disorder is one of the most lethal of all psychiatric disorders, these study findings could have a major impact on public health.
“Our finding that a single infusion of ketamine produces rapid antidepressant and antisuicidal effects within one hour and that is fairly sustained is truly exciting,” Dr. Zarate commented. “We think that these findings are of true importance given that we only have a few treatments approved for acute bipolar depression, and none of them have this rapid onset of action; they usually take weeks or longer to have comparable antidepressant effects as ketamine does.”
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, which means that it works by blocking the actions of NMDA. Dr. Zarate added, “Importantly, confirmation that blocking the NMDA receptor complex is involved in generating rapid antidepressant and antisuicidal effects offers an avenue for developing the next generation of treatments for depression that are radically different than existing ones.”
The article is “Replication of Ketamine’s Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial” by Carlos A. Zarate Jr., Nancy E. Brutsche, Lobna Ibrahim, Jose Franco-Chaves, Nancy Diazgranados, Anibal Cravchik, Jessica Selter, Craig A. Marquardt, Victoria Liberty, and David A. Luckenbaugh (doi: 10.1016/j.biopsych.2011.12.010). The article appears in Biological Psychiatry, Volume 71, Issue 11 (June 1, 2012)
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Map 22035 Fairfax Fairfax – 22036 Fairfax Fairfax – 22037 Fairfax Fairfax – 22038 Fairfax Fairfax City – 22039 Fairfax Station Fairfax – 22040 Falls Church Falls Church City – 22041 Falls Church Fairfax – 22042 Falls Church Fairfax – 22043 Falls Church Fairfax – 22044 Falls Church Fairfax – 22046 Falls Church Falls Church City – 22047 Falls Church Fairfax – 22060 Fort Belvoir Fairfax – 22066 Great Falls Fairfax – 22067 Greenway Fairfax – 22079 Lorton Fairfax – 22081 Merrifield Fairfax – 22082 Merrifield Fairfax – 22092 Herndon Fairfax View
Map 22093 Ashburn Loudoun – 22095 Herndon Fairfax – 22096 Reston Fairfax – 22101 Mc Lean Fairfax – 22102 Mc Lean Fairfax – 22103 West Mclean Fairfax – 22106 Mc Lean Fairfax – 22107 Mc Lean Fairfax – 22108 Mc Lean Fairfax – 22109 Mc Lean Fairfax – 22116 Merrifield Fairfax – 22118 Merrifield Fairfax – 22119 Merrifield Fairfax – 22120 Merrifield Fairfax – 22121 Mount Vernon Fairfax – 22122 Newington Fairfax – 22124 Oakton Fairfax – 22125 Occoquan Prince William – 22134 Quantico Prince William View
Map 22135 Quantico Stafford – 22150 Springfield Fairfax – 22151 Springfield Fairfax – 22152 Springfield Fairfax – 22153 Springfield Fairfax – 22156 Springfield Fairfax – 22158 Springfield Fairfax – 22159 Springfield Fairfax – 22160 Springfield Fairfax – 22161 Springfield Fairfax – 22172 Triangle Prince William – 22180 Vienna Fairfax – 22181 Vienna Fairfax – 22182 Vienna Fairfax – 22183 Vienna Fairfax – 22184 Vienna Fairfax – 22185 Vienna Fairfax – 22191 Woodbridge Prince William – 22192 Woodbridge Prince William View
Map 22193 Woodbridge Prince William – 22194 Woodbridge Prince William – 22195 Woodbridge Prince William – 22199 Lorton Fairfax – 22201 Arlington Arlington – 22202 Arlington Arlington – 22203 Arlington Arlington – 22204 Arlington Arlington – 22205 Arlington Arlington – 22206 Arlington Arlington – 22207 Arlington Arlington – 22209 Arlington Arlington – 22210 Arlington Arlington – 22211 Ft Myer Arlington – 22212 Arlington Arlington – 22213 Arlington Arlington – 22214 Arlington Arlington – 22215 Arlington Arlington – 22216 Arlington Arlington View
Map 22217 Arlington Arlington – 22218 Arlington Arlington – 22219 Arlington Arlington – 22222 Arlington Arlington – 22223 Arlington Arlington – 22225 Arlington Arlington – 22226 Arlington Arlington – 22227 Arlington Arlington – 22229 Arlington Arlington – 22230 Arlington Arlington – 22234 Arlington Arlington – 22240 Arlington Arlington – 22241 Arlington Arlington – 22242 Arlington Arlington – 22243 Arlington Arlington – 22244 Arlington Arlington – 22245 Arlington Arlington – 22246 Arlington Arlington – 22301 Alexandria Alexandria City View
Map 22302 Alexandria Alexandria City – 22303 Alexandria Fairfax – 22304 Alexandria Alexandria City – 22305 Alexandria Alexandria City – 22306 Alexandria Fairfax – 22307 Alexandria Fairfax – 22308 Alexandria Fairfax – 22309 Alexandria Fairfax – 22310 Alexandria Fairfax – 22311 Alexandria Alexandria City – 22312 Alexandria Fairfax – 22313 Alexandria Alexandria City – 22314 Alexandria Alexandria City – 22315 Alexandria Fairfax – 22320 Alexandria Alexandria City – 22321 Alexandria Fairfax – 22331 Alexandria Alexandria City – 22332 Alexandria Alexandria City – 22333 Alexandria Alexandria City View
Map 22334 Alexandria Alexandria City – 22336 Alexandria Alexandria City – 22401 Fredericksburg Fredericksburg City – 22402 Fredericksburg Fredericksburg City – 22403 Fredericksburg Stafford – 22404 Fredericksburg Fredericksburg City – 22405 Fredericksburg Stafford – 22406 Fredericksburg Stafford – 22407 Fredericksburg Spotsylvania – 22408 Fredericksburg Spotsylvania – 22412 Fredericksburg Stafford – 22427 Bowling Green Caroline – 22428 Bowling Green Caroline – 22430 Brooke Stafford – 22432 Burgess Northumberland – 22433 Burr Hill Orange – 22435 Callao Northumberland – 22436 Caret Essex – 22437 Center Cross Essex View
Map 22438 Champlain Essex – 22442 Coles Point Westmoreland – 22443 Colonial Beach Westmoreland – 22446 Corbin Caroline – 22448 Dahlgren King George – 22451 Dogue King George – 22454 Dunnsville Essex – 22456 Edwardsville Northumberland – 22460 Farnham Richmond – 22463 Garrisonville Stafford – 22469 Hague Westmoreland – 22471 Hartwood Stafford – 22472 Haynesville Richmond – 22473 Heathsville Northumberland – 22476 Hustle Essex – 22480 Irvington Lancaster – 22481 Jersey King George – 22482 Kilmarnock Lancaster – 22485 King George King George View
Map 22488 Kinsale Westmoreland – 22501 Ladysmith Caroline – 22503 Lancaster Lancaster – 22504 Laneview Essex – 22507 Lively Lancaster – 22508 Locust Grove Orange – 22509 Loretto Essex – 22511 Lottsburg Northumberland – 22513 Merry Point Lancaster – 22514 Milford Caroline – 22517 Mollusk Lancaster – 22520 Montross Westmoreland – 22523 Morattico Lancaster – 22524 Mount Holly Westmoreland – 22526 Ninde King George – 22528 Nuttsville Lancaster – 22529 Oldhams Westmoreland – 22530 Ophelia Northumberland – 22534 Partlow Spotsylvania View
Map 22535 Port Royal Caroline – 22538 Rappahannock Academy Caroline – 22539 Reedville Northumberland – 22542 Rhoadesville Orange – 22544 Rollins Fork King George – 22545 Ruby Stafford – 22546 Ruther Glen Caroline – 22547 Sealston King George – 22548 Sharps Richmond – 22552 Sparta Caroline – 22553 Spotsylvania Spotsylvania – 22554 Stafford Stafford – 22555 Stafford Stafford – 22556 Stafford Stafford – 22558 Stratford Westmoreland – 22560 Tappahannock Essex – 22565 Thornburg Spotsylvania – 22567 Unionville Orange – 22570 Village Richmond View
Map 22572 Warsaw Richmond – 22576 Weems Lancaster – 22577 Sandy Point Westmoreland – 22578 White Stone Lancaster – 22579 Wicomico Church Northumberland – 22580 Woodford Caroline – 22581 Zacata Westmoreland – 22601 Winchester Winchester City – 22602 Winchester Frederick – 22603 Winchester Frederick – 22604 Winchester Winchester City – 22610 Bentonville Warren – 22611 Berryville Clarke – 22620 Boyce Clarke – 22622 Brucetown Frederick – 22623 Chester Gap Rappahannock – 22624 Clear Brook Frederick – 22625 Cross Junction Frederick – 22626 Fishers Hill Shenandoah View
Map 22627 Flint Hill Rappahannock – 22630 Front Royal Warren – 22637 Gore Frederick – 22638 Winchester Frederick – 22639 Hume Fauquier – 22640 Huntly Rappahannock – 22641 Strasburg Shenandoah – 22642 Linden Warren – 22643 Markham Fauquier – 22644 Maurertown Shenandoah – 22645 Middletown Frederick – 22646 Millwood Clarke – 22649 Middletown Warren – 22650 Rileyville Page – 22652 Fort Valley Shenandoah – 22654 Star Tannery Frederick – 22655 Stephens City Frederick – 22656 Stephenson Frederick – 22657 Strasburg Shenandoah View
Map 22660 Toms Brook Shenandoah – 22663 White Post Clarke – 22664 Woodstock Shenandoah – 22701 Culpeper Culpeper – 22709 Aroda Madison – 22711 Banco Madison – 22712 Bealeton Fauquier – 22713 Boston Culpeper – 22714 Brandy Station Culpeper – 22715 Brightwood Madison – 22716 Castleton Rappahannock – 22718 Elkwood Culpeper – 22719 Etlan Madison – 22720 Goldvein Fauquier – 22721 Graves Mill Madison – 22722 Haywood Madison – 22723 Hood Madison – 22724 Jeffersonton Culpeper – 22725 Leon Madison View
Map 22726 Lignum Culpeper – 22727 Madison Madison – 22728 Midland Fauquier – 22729 Mitchells Culpeper – 22730 Oakpark Madison – 22731 Pratts Madison – 22732 Radiant Madison – 22733 Rapidan Culpeper – 22734 Remington Fauquier – 22735 Reva Madison – 22736 Richardsville Culpeper – 22737 Rixeyville Culpeper – 22738 Rochelle Madison – 22739 Somerville Fauquier – 22740 Sperryville Rappahannock – 22741 Stevensburg Culpeper – 22742 Sumerduck Fauquier – 22743 Syria Madison – 22746 Viewtown Culpeper View
Map 22747 Washington Rappahannock – 22748 Wolftown Madison – 22749 Woodville Rappahannock – 22801 Harrisonburg Harrisonburg City – 22802 Harrisonburg Harrisonburg City – 22803 Harrisonburg Harrisonburg City – 22807 Harrisonburg Harrisonburg City – 22810 Basye Shenandoah – 22811 Bergton Rockingham – 22812 Bridgewater Rockingham – 22815 Broadway Rockingham – 22820 Criders Rockingham – 22821 Dayton Rockingham – 22824 Edinburg Shenandoah – 22827 Elkton Rockingham – 22830 Fulks Run Rockingham – 22831 Hinton Rockingham – 22832 Keezletown Rockingham – 22833 Lacey Spring Rockingham View
Map 22834 Linville Rockingham – 22835 Luray Page – 22840 Mc Gaheysville Rockingham – 22841 Mount Crawford Rockingham – 22842 Mount Jackson Shenandoah – 22843 Mount Solon Augusta – 22844 New Market Shenandoah – 22845 Orkney Springs Shenandoah – 22846 Penn Laird Rockingham – 22847 Quicksburg Shenandoah – 22848 Pleasant Valley Rockingham – 22849 Shenandoah Page – 22850 Singers Glen Rockingham – 22851 Stanley Page – 22853 Timberville Rockingham – 22901 Charlottesville Albemarle – 22902 Charlottesville Charlottesville City – 22903 Charlottesville Charlottesville City – 22904 Charlottesville Charlottesville City View
Map 22905 Charlottesville Charlottesville City – 22906 Charlottesville Charlottesville City – 22907 Charlottesville Charlottesville City – 22908 Charlottesville Charlottesville City – 22909 Charlottesville Albemarle – 22910 Charlottesville Charlottesville City – 22911 Charlottesville Albemarle – 22920 Afton Nelson – 22922 Arrington Nelson – 22923 Barboursville Orange – 22924 Batesville Albemarle – 22931 Covesville Albemarle – 22932 Crozet Albemarle – 22935 Dyke Greene – 22936 Earlysville Albemarle – 22937 Esmont Albemarle – 22938 Faber Nelson – 22939 Fishersville Augusta – 22940 Free Union Albemarle View
Map 22942 Gordonsville Orange – 22943 Greenwood Albemarle – 22945 Ivy Albemarle – 22946 Keene Albemarle – 22947 Keswick Albemarle – 22948 Locust Dale Madison – 22949 Lovingston Nelson – 22952 Lyndhurst Augusta – 22957 Montpelier Station Orange – 22958 Nellysford Nelson – 22959 North Garden Albemarle – 22960 Orange Orange – 22963 Palmyra Fluvanna – 22964 Piney River Nelson – 22965 Quinque Greene – 22967 Roseland Nelson – 22968 Ruckersville Greene – 22969 Schuyler Nelson – 22971 Shipman Nelson View
Map 22972 Somerset Orange – 22973 Stanardsville Greene – 22974 Troy Fluvanna – 22976 Tyro Nelson – 22980 Waynesboro Waynesboro City – 22987 White Hall Albemarle – 22989 Woodberry Forest Madison – 23001 Achilles Gloucester – 23002 Amelia Court House Amelia – 23003 Ark Gloucester – 23004 Arvonia Buckingham – 23005 Ashland Hanover – 23009 Aylett King William – 23011 Barhamsville New Kent – 23014 Beaumont Goochland – 23015 Beaverdam Hanover – 23018 Bena Gloucester – 23021 Bohannon Mathews – 23022 Bremo Bluff Fluvanna View
Map 23023 Bruington King And Queen – 23024 Bumpass Louisa – 23025 Cardinal Mathews – 23027 Cartersville Cumberland – 23030 Charles City Charles City – 23031 Christchurch Middlesex – 23032 Church View Middlesex – 23035 Cobbs Creek Mathews – 23038 Columbia Goochland – 23039 Crozier Goochland – 23040 Cumberland Cumberland – 23043 Deltaville Middlesex – 23045 Diggs Mathews – 23047 Doswell Hanover – 23050 Dutton Gloucester – 23055 Fork Union Fluvanna – 23056 Foster Mathews – 23058 Glen Allen Henrico – 23059 Glen Allen Henrico View
Map 23060 Glen Allen Henrico – 23061 Gloucester Gloucester – 23062 Gloucester Point Gloucester – 23063 Goochland Goochland – 23064 Grimstead Mathews – 23065 Gum Spring Goochland – 23066 Gwynn Mathews – 23067 Hadensville Goochland – 23068 Hallieford Mathews – 23069 Hanover Hanover – 23070 Hardyville Middlesex – 23071 Hartfield Middlesex – 23072 Hayes Gloucester – 23075 Highland Springs Henrico – 23076 Hudgins Mathews – 23079 Jamaica Middlesex – 23081 Jamestown James City – 23083 Jetersville Amelia – 23084 Kents Store Fluvanna View
Map 23085 King And Queen Court House King And Queen – 23086 King William King William – 23089 Lanexa New Kent – 23090 Lightfoot York – 23091 Little Plymouth King And Queen – 23092 Locust Hill Middlesex – 23093 Louisa Louisa – 23101 Macon Powhatan – 23102 Maidens Goochland – 23103 Manakin Sabot Goochland – 23105 Mannboro Amelia – 23106 Manquin King William – 23107 Maryus Gloucester – 23108 Mascot King And Queen – 23109 Mathews Mathews – 23110 Mattaponi King And Queen – 23111 Mechanicsville Hanover – 23112 Midlothian Chesterfield – 23113 Midlothian Chesterfield View
Map 23114 Midlothian Chesterfield – 23115 Millers Tavern Essex – 23116 Mechanicsville Hanover – 23117 Mineral Louisa – 23119 Moon Mathews – 23120 Moseley Chesterfield – 23123 New Canton Buckingham – 23124 New Kent New Kent – 23125 New Point Mathews – 23126 Newtown King And Queen – 23127 Norge James City – 23128 North Mathews – 23129 Oilville Goochland – 23130 Onemo Mathews – 23131 Ordinary Gloucester – 23138 Port Haywood Mathews – 23139 Powhatan Powhatan – 23140 Providence Forge New Kent – 23141 Quinton New Kent View
Map 23146 Rockville Hanover – 23147 Ruthville Charles City – 23148 Saint Stephens Church King And Queen – 23149 Saluda Middlesex – 23150 Sandston Henrico – 23153 Sandy Hook Goochland – 23154 Schley Gloucester – 23155 Severn Gloucester – 23156 Shacklefords King And Queen – 23160 State Farm Goochland – 23161 Stevensville King And Queen – 23162 Studley Hanover – 23163 Susan Mathews – 23168 Toano James City – 23169 Topping Middlesex – 23170 Trevilians Louisa – 23173 University Of Richmond Richmond City – 23175 Urbanna Middlesex – 23176 Wake Middlesex View
Map 23177 Walkerton King And Queen – 23178 Ware Neck Gloucester – 23180 Water View Middlesex – 23181 West Point King William – 23183 White Marsh Gloucester – 23184 Wicomico Gloucester – 23185 Williamsburg James City – 23186 Williamsburg Williamsburg City – 23187 Williamsburg Williamsburg City – 23188 Williamsburg James City – 23190 Woods Cross Roads Gloucester – 23192 Montpelier Hanover – 23218 Richmond Richmond City – 23219 Richmond Richmond City – 23220 Richmond Richmond City – 23221 Richmond Richmond City – 23222 Richmond Richmond City – 23223 Richmond Richmond City – 23224 Richmond Richmond City View
Map 23225 Richmond Richmond City – 23226 Richmond Henrico – 23227 Richmond Henrico – 23228 Richmond Henrico – 23229 Richmond Henrico – 23230 Richmond Henrico – 23231 Richmond Henrico – 23232 Richmond Richmond City – 23233 Richmond Henrico – 23234 Richmond Chesterfield – 23235 Richmond Chesterfield – 23236 Richmond Chesterfield – 23237 Richmond Chesterfield – 23238 Richmond Henrico – 23240 Richmond Richmond City – 23241 Richmond Richmond City – 23242 Richmond Henrico – 23249 Richmond Richmond City – 23250 Richmond Henrico View
Map 23255 Richmond Henrico – 23260 Richmond Richmond City – 23261 Richmond Richmond City – 23269 Richmond Richmond City – 23273 Richmond Richmond City – 23274 Richmond Richmond City – 23276 Richmond Richmond City – 23278 Richmond Richmond City – 23279 Richmond Richmond City – 23282 Richmond Richmond City – 23284 Richmond Richmond City – 23285 Richmond Richmond City – 23286 Richmond Richmond City – 23288 Richmond Henrico – 23289 Richmond Richmond City – 23290 Richmond Richmond City – 23291 Richmond Richmond City – 23292 Richmond Richmond City – 23293 Richmond Richmond City View
Map 23294 Richmond Henrico – 23295 Richmond Richmond City – 23297 Richmond Chesterfield – 23298 Richmond Richmond City – 23301 Accomac Accomack – 23302 Assawoman Accomack – 23303 Atlantic Accomack – 23304 Battery Park Isle Of Wight – 23306 Belle Haven Accomack – 23307 Birdsnest Northampton – 23308 Bloxom Accomack – 23310 Cape Charles Northampton – 23313 Capeville Northampton – 23314 Carrollton Isle Of Wight – 23315 Carrsville Isle Of Wight – 23316 Cheriton Northampton – 23320 Chesapeake Chesapeake City – 23321 Chesapeake Chesapeake City – 23322 Chesapeake Chesapeake City View
Map 23323 Chesapeake Chesapeake City – 23324 Chesapeake Chesapeake City – 23325 Chesapeake Chesapeake City – 23326 Chesapeake Chesapeake City – 23327 Chesapeake Chesapeake City – 23328 Chesapeake Chesapeake City – 23336 Chincoteague Island Accomack – 23337 Wallops Island Accomack – 23341 Craddockville Accomack – 23345 Davis Wharf Accomack – 23347 Eastville Northampton – 23350 Exmore Northampton – 23354 Franktown Northampton – 23356 Greenbackville Accomack – 23357 Greenbush Accomack – 23358 Hacksneck Accomack – 23359 Hallwood Accomack – 23389 Harborton Accomack – 23395 Horntown Accomack View
Map 23396 Oak Hall Accomack – 23397 Isle Of Wight Isle Of Wight – 23398 Jamesville Northampton – 23399 Jenkins Bridge Accomack – 23401 Keller Accomack – 23404 Locustville Accomack – 23405 Machipongo Northampton – 23407 Mappsville Accomack – 23408 Marionville Northampton – 23409 Mears Accomack – 23410 Melfa Accomack – 23412 Modest Town Accomack – 23413 Nassawadox Northampton – 23414 Nelsonia Accomack – 23415 New Church Accomack – 23416 Oak Hall Accomack – 23417 Onancock Accomack – 23418 Onley Accomack – 23419 Oyster Northampton View
Map 23420 Painter Accomack – 23421 Parksley Accomack – 23422 Pungoteague Accomack – 23423 Quinby Accomack – 23424 Rescue Isle Of Wight – 23426 Sanford Accomack – 23427 Saxis Accomack – 23429 Seaview Northampton – 23430 Smithfield Isle Of Wight – 23431 Smithfield Isle Of Wight – 23432 Suffolk Suffolk City – 23433 Suffolk Suffolk City – 23434 Suffolk Suffolk City – 23435 Suffolk Suffolk City – 23436 Suffolk Suffolk City – 23437 Suffolk Suffolk City – 23438 Suffolk Suffolk City – 23439 Suffolk Suffolk City – 23440 Tangier Accomack View
Map 23441 Tasley Accomack – 23442 Temperanceville Accomack – 23443 Townsend Northampton – 23450 Virginia Beach Virginia Beach City – 23451 Virginia Beach Virginia Beach City – 23452 Virginia Beach Virginia Beach City – 23453 Virginia Beach Virginia Beach City – 23454 Virginia Beach Virginia Beach City – 23455 Virginia Beach Virginia Beach City – 23456 Virginia Beach Virginia Beach City – 23457 Virginia Beach Virginia Beach City – 23458 Virginia Beach Virginia Beach City – 23459 Virginia Beach Virginia Beach City – 23460 Virginia Beach Virginia Beach City – 23461 Virginia Beach Virginia Beach City – 23462 Virginia Beach Virginia Beach City – 23463 Virginia Beach Virginia Beach City – 23464 Virginia Beach Virginia Beach City – 23465 Virginia Beach Virginia Beach City View
Map 23466 Virginia Beach Virginia Beach City – 23467 Virginia Beach Virginia Beach City – 23471 Virginia Beach Virginia Beach City – 23479 Virginia Beach Virginia Beach City – 23480 Wachapreague Accomack – 23482 Wardtown Northampton – 23483 Wattsville Accomack – 23486 Willis Wharf Northampton – 23487 Windsor Isle Of Wight – 23488 Withams Accomack – 23501 Norfolk Norfolk City – 23502 Norfolk Norfolk City – 23503 Norfolk Norfolk City – 23504 Norfolk Norfolk City – 23505 Norfolk Norfolk City – 23506 Norfolk Norfolk City – 23507 Norfolk Norfolk City – 23508 Norfolk Norfolk City – 23509 Norfolk Norfolk City View
Map 23510 Norfolk Norfolk City – 23511 Norfolk Norfolk City – 23512 Norfolk Norfolk City – 23513 Norfolk Norfolk City – 23514 Norfolk Norfolk City – 23515 Norfolk Norfolk City – 23517 Norfolk Norfolk City – 23518 Norfolk Norfolk City – 23519 Norfolk Norfolk City – 23520 Norfolk Norfolk City – 23521 Norfolk Norfolk City – 23523 Norfolk Norfolk City – 23529 Norfolk Norfolk City – 23541 Norfolk Norfolk City – 23551 Norfolk Norfolk City – 23601 Newport News Newport News City – 23602 Newport News Newport News City – 23603 Newport News Newport News City – 23604 Fort Eustis Newport News City View
Map 23605 Newport News Newport News City – 23606 Newport News Newport News City – 23607 Newport News Newport News City – 23608 Newport News Newport News City – 23609 Newport News Newport News City – 23612 Newport News Newport News City – 23628 Newport News Newport News City – 23630 Hampton Hampton City – 23651 Fort Monroe Hampton City – 23661 Hampton Hampton City – 23662 Poquoson Poquoson City – 23663 Hampton Hampton City – 23664 Hampton Hampton City – 23665 Hampton York – 23666 Hampton Hampton City – 23667 Hampton Hampton City – 23668 Hampton Hampton City – 23669 Hampton Hampton City – 23670 Hampton Hampton City View
Map 23681 Hampton Hampton City – 23690 Yorktown York – 23691 Yorktown York – 23692 Yorktown York – 23693 Yorktown York – 23694 Lackey York – 23696 Seaford York – 23701 Portsmouth Portsmouth City – 23702 Portsmouth Portsmouth City – 23703 Portsmouth Portsmouth City – 23704 Portsmouth Portsmouth City – 23705 Portsmouth Portsmouth City – 23707 Portsmouth Portsmouth City – 23708 Portsmouth Portsmouth City – 23709 Portsmouth Portsmouth City – 23801 Fort Lee Prince George – 23803 Petersburg Petersburg City – 23804 Petersburg Petersburg City – 23805 Petersburg Petersburg City View
Map 23806 Petersburg Petersburg City – 23821 Alberta Brunswick – 23822 Ammon Dinwiddie – 23824 Blackstone Nottoway – 23825 Blackstone Nottoway – 23827 Boykins Southampton – 23828 Branchville Southampton – 23829 Capron Southampton – 23830 Carson Dinwiddie – 23831 Chester Chesterfield – 23832 Chesterfield Chesterfield – 23833 Church Road Dinwiddie – 23834 Colonial Heights Colonial Heights City – 23836 Chester Chesterfield – 23837 Courtland Southampton – 23838 Chesterfield Chesterfield – 23839 Dendron Surry – 23840 Dewitt Dinwiddie – 23841 Dinwiddie Dinwiddie View
Map 23842 Disputanta Prince George – 23843 Dolphin Brunswick – 23844 Drewryville Southampton – 23845 Ebony Brunswick – 23846 Elberon Surry – 23847 Emporia Greensville – 23850 Ford Dinwiddie – 23851 Franklin Franklin City – 23856 Freeman Brunswick – 23857 Gasburg Brunswick – 23860 Hopewell Hopewell City – 23866 Ivor Southampton – 23867 Jarratt Greensville – 23868 Lawrenceville Brunswick – 23870 Jarratt Greensville – 23872 Mc Kenney Dinwiddie – 23873 Meredithville Brunswick – 23874 Newsoms Southampton – 23875 Prince George Prince George View
Map 23876 Rawlings Brunswick – 23878 Sedley Southampton – 23879 Skippers Greensville – 23881 Spring Grove Surry – 23882 Stony Creek Sussex – 23883 Surry Surry – 23884 Sussex Sussex – 23885 Sutherland Dinwiddie – 23887 Valentines Brunswick – 23888 Wakefield Sussex – 23889 Warfield Brunswick – 23890 Waverly Sussex – 23891 Waverly Sussex – 23893 White Plains Brunswick – 23894 Wilsons Dinwiddie – 23897 Yale Sussex – 23898 Zuni Isle Of Wight – 23899 Claremont Surry – 23901 Farmville Prince Edward View
Map 23909 Farmville Prince Edward – 23915 Baskerville Mecklenburg – 23917 Boydton Mecklenburg – 23919 Bracey Mecklenburg – 23920 Brodnax Brunswick – 23921 Buckingham Buckingham – 23922 Burkeville Nottoway – 23923 Charlotte Court House Charlotte – 23924 Chase City Mecklenburg – 23927 Clarksville Mecklenburg – 23930 Crewe Nottoway – 23934 Cullen Charlotte – 23936 Dillwyn Buckingham – 23937 Drakes Branch Charlotte – 23938 Dundas Lunenburg – 23939 Evergreen Appomattox – 23941 Fort Mitchell Lunenburg – 23942 Green Bay Prince Edward – 23943 Hampden Sydney Prince Edward View
Map 23944 Kenbridge Lunenburg – 23947 Keysville Charlotte – 23950 La Crosse Mecklenburg – 23952 Lunenburg Lunenburg – 23954 Meherrin Prince Edward – 23955 Nottoway Nottoway – 23958 Pamplin Appomattox – 23959 Phenix Charlotte – 23960 Prospect Prince Edward – 23962 Randolph Charlotte – 23963 Red House Charlotte – 23964 Red Oak Charlotte – 23966 Rice Prince Edward – 23967 Saxe Charlotte – 23968 Skipwith Mecklenburg – 23970 South Hill Mecklenburg – 23974 Victoria Lunenburg – 23976 Wylliesburg Charlotte – 24001 Roanoke Roanoke City View
Map 24002 Roanoke Roanoke City – 24003 Roanoke Roanoke City – 24004 Roanoke Roanoke City – 24005 Roanoke Roanoke City – 24006 Roanoke Roanoke City – 24007 Roanoke Roanoke City – 24008 Roanoke Roanoke City – 24009 Roanoke Roanoke City – 24010 Roanoke Roanoke City – 24011 Roanoke Roanoke City – 24012 Roanoke Roanoke City – 24013 Roanoke Roanoke City – 24014 Roanoke Roanoke City – 24015 Roanoke Roanoke City – 24016 Roanoke Roanoke City – 24017 Roanoke Roanoke City – 24018 Roanoke Roanoke – 24019 Roanoke Roanoke – 24020 Roanoke Roanoke View
Map 24022 Roanoke Roanoke City – 24023 Roanoke Roanoke City – 24024 Roanoke Roanoke City – 24025 Roanoke Roanoke City – 24026 Roanoke Roanoke City – 24027 Roanoke Roanoke City – 24028 Roanoke Roanoke City – 24029 Roanoke Roanoke City – 24030 Roanoke Roanoke City – 24031 Roanoke Roanoke City – 24032 Roanoke Roanoke City – 24033 Roanoke Roanoke City – 24034 Roanoke Roanoke City – 24035 Roanoke Roanoke City – 24036 Roanoke Roanoke City – 24037 Roanoke Roanoke City – 24038 Roanoke Roanoke City – 24040 Roanoke Roanoke City – 24042 Roanoke Roanoke City View
Map 24043 Roanoke Roanoke City – 24044 Roanoke Roanoke City – 24045 Roanoke Roanoke City – 24048 Roanoke Roanoke City – 24050 Roanoke Botetourt – 24053 Ararat Patrick – 24054 Axton Henry – 24055 Bassett Henry – 24058 Belspring Pulaski – 24059 Bent Mountain Roanoke – 24060 Blacksburg Montgomery – 24061 Blacksburg Montgomery – 24062 Blacksburg Montgomery – 24063 Blacksburg Montgomery – 24064 Blue Ridge Botetourt – 24065 Boones Mill Franklin – 24066 Buchanan Botetourt – 24067 Callaway Franklin – 24068 Christiansburg Montgomery View
Map 24069 Cascade Pittsylvania – 24070 Catawba Roanoke – 24072 Check Floyd – 24073 Christiansburg Montgomery – 24076 Claudville Patrick – 24077 Cloverdale Botetourt – 24078 Collinsville Henry – 24079 Copper Hill Floyd – 24082 Critz Patrick – 24083 Daleville Botetourt – 24084 Dublin Pulaski – 24085 Eagle Rock Botetourt – 24086 Eggleston Giles – 24087 Elliston Montgomery – 24088 Ferrum Franklin – 24089 Fieldale Henry – 24090 Fincastle Botetourt – 24091 Floyd Floyd – 24092 Glade Hill Franklin View
Map 24093 Glen Lyn Giles – 24095 Goodview Bedford – 24101 Hardy Franklin – 24102 Henry Franklin – 24104 Huddleston Bedford – 24105 Indian Valley Floyd – 24111 Mc Coy Montgomery – 24112 Martinsville Martinsville City – 24113 Martinsville Martinsville City – 24114 Martinsville Martinsville City – 24115 Martinsville Martinsville City – 24120 Meadows Of Dan Patrick – 24121 Moneta Bedford – 24122 Montvale Bedford – 24124 Narrows Giles – 24126 Newbern Pulaski – 24127 New Castle Craig – 24128 Newport Giles – 24129 New River Pulaski View
Map 24130 Oriskany Botetourt – 24131 Paint Bank Craig – 24132 Parrott Pulaski – 24133 Patrick Springs Patrick – 24134 Pearisburg Giles – 24136 Pembroke Giles – 24137 Penhook Franklin – 24138 Pilot Montgomery – 24139 Pittsville Pittsylvania – 24141 Radford Radford – 24142 Radford Radford – 24143 Radford Radford – 24146 Redwood Franklin – 24147 Rich Creek Giles – 24148 Ridgeway Henry – 24149 Riner Montgomery – 24150 Ripplemead Giles – 24151 Rocky Mount Franklin – 24153 Salem Salem View
Map 24155 Roanoke Salem – 24157 Roanoke Salem – 24161 Sandy Level Pittsylvania – 24162 Shawsville Montgomery – 24165 Spencer Henry – 24167 Staffordsville Giles – 24168 Stanleytown Henry – 24171 Stuart Patrick – 24174 Thaxton Bedford – 24175 Troutville Botetourt – 24176 Union Hall Franklin – 24177 Vesta Patrick – 24178 Villamont Bedford – 24179 Vinton Roanoke – 24184 Wirtz Franklin – 24185 Woolwine Patrick – 24201 Bristol Bristol – 24202 Bristol Washington – 24203 Bristol Bristol View
Map 24209 Bristol Bristol – 24210 Abingdon Washington – 24211 Abingdon Washington – 24212 Abingdon Washington – 24215 Andover Wise – 24216 Appalachia Wise – 24217 Bee Dickenson – 24218 Ben Hur Lee – 24219 Big Stone Gap Wise – 24220 Birchleaf Dickenson – 24221 Blackwater Lee – 24224 Castlewood Russell – 24225 Cleveland Russell – 24226 Clinchco Dickenson – 24228 Clintwood Dickenson – 24230 Coeburn Wise – 24236 Damascus Washington – 24237 Dante Russell – 24239 Davenport Buchanan View
Map 24243 Dryden Lee – 24244 Duffield Scott – 24245 Dungannon Scott – 24246 East Stone Gap Wise – 24248 Ewing Lee – 24250 Fort Blackmore Scott – 24251 Gate City Scott – 24256 Haysi Dickenson – 24258 Hiltons Scott – 24260 Honaker Russell – 24263 Jonesville Lee – 24265 Keokee Lee – 24266 Lebanon Russell – 24269 Mc Clure Dickenson – 24270 Mendota Washington – 24271 Nickelsville Scott – 24272 Nora Dickenson – 24273 Norton Norton City – 24277 Pennington Gap Lee View
Map 24279 Pound Wise – 24280 Rosedale Russell – 24281 Rose Hill Lee – 24282 Saint Charles Lee – 24283 Saint Paul Wise – 24290 Weber City Scott – 24292 Whitetop Grayson – 24293 Wise Wise – 24301 Pulaski Pulaski – 24311 Atkins Smyth – 24312 Austinville Wythe – 24313 Barren Springs Wythe – 24314 Bastian Bland – 24315 Bland Bland – 24316 Broadford Tazewell – 24317 Cana Carroll – 24318 Ceres Bland – 24319 Chilhowie Smyth – 24322 Cripple Creek Wythe View
Map 24323 Crockett Wythe – 24324 Draper Pulaski – 24325 Dugspur Carroll – 24326 Elk Creek Grayson – 24327 Emory Washington – 24328 Fancy Gap Carroll – 24330 Fries Grayson – 24333 Galax Galax City – 24340 Glade Spring Washington – 24343 Hillsville Carroll – 24347 Hiwassee Pulaski – 24348 Independence Grayson – 24350 Ivanhoe Wythe – 24351 Lambsburg Carroll – 24352 Laurel Fork Carroll – 24354 Marion Smyth – 24360 Max Meadows Wythe – 24361 Meadowview Washington – 24363 Mouth Of Wilson Grayson View
Map 24366 Rocky Gap Bland – 24368 Rural Retreat Wythe – 24370 Saltville Smyth – 24374 Speedwell Wythe – 24375 Sugar Grove Smyth – 24377 Tannersville Tazewell – 24378 Troutdale Grayson – 24380 Willis Floyd – 24381 Woodlawn Carroll – 24382 Wytheville Wythe – 24401 Staunton Staunton City – 24402 Staunton Staunton City – 24411 Augusta Springs Augusta – 24412 Bacova Bath – 24413 Blue Grass Highland – 24415 Brownsburg Rockbridge – 24416 Buena Vista Buena Vista City – 24421 Churchville Augusta – 24422 Clifton Forge Alleghany View
Map 24426 Covington Covington City – 24430 Craigsville Augusta – 24431 Crimora Augusta – 24432 Deerfield Augusta – 24433 Doe Hill Highland – 24435 Fairfield Rockbridge – 24437 Fort Defiance Augusta – 24438 Glen Wilton Botetourt – 24439 Goshen Rockbridge – 24440 Greenville Augusta – 24441 Grottoes Rockingham – 24442 Head Waters Highland – 24445 Hot Springs Bath – 24448 Iron Gate Alleghany – 24450 Lexington Lexington City – 24457 Low Moor Alleghany – 24458 Mc Dowell Highland – 24459 Middlebrook Augusta – 24460 Millboro Bath View
Map 24463 Mint Spring Augusta – 24464 Montebello Nelson – 24465 Monterey Highland – 24467 Mount Sidney Augusta – 24468 Mustoe Highland – 24469 New Hope Augusta – 24471 Port Republic Rockingham – 24472 Raphine Rockbridge – 24473 Rockbridge Baths Rockbridge – 24474 Selma Alleghany – 24476 Steeles Tavern Augusta – 24477 Stuarts Draft Augusta – 24479 Swoope Augusta – 24482 Verona Augusta – 24483 Vesuvius Rockbridge – 24484 Warm Springs Bath – 24485 West Augusta Augusta – 24486 Weyers Cave Augusta – 24487 Williamsville Bath View
Map 24501 Lynchburg Lynchburg City – 24502 Lynchburg Lynchburg City – 24503 Lynchburg Lynchburg City – 24504 Lynchburg Lynchburg City – 24505 Lynchburg Lynchburg City – 24506 Lynchburg Lynchburg City – 24512 Lynchburg Lynchburg City – 24513 Lynchburg Lynchburg City – 24514 Lynchburg Lynchburg City – 24515 Lynchburg Lynchburg City – 24517 Altavista Campbell – 24520 Alton Halifax – 24521 Amherst Amherst – 24522 Appomattox Appomattox – 24523 Bedford Bedford – 24526 Big Island Bedford – 24527 Blairs Pittsylvania – 24528 Brookneal Campbell – 24529 Buffalo Junction Mecklenburg View
Map 24530 Callands Pittsylvania – 24531 Chatham Pittsylvania – 24533 Clifford Amherst – 24534 Clover Halifax – 24535 Cluster Springs Halifax – 24536 Coleman Falls Bedford – 24538 Concord Campbell – 24539 Crystal Hill Halifax – 24540 Danville Danville City – 24541 Danville Danville City – 24543 Danville Danville City – 24544 Danville Danville City – 24549 Dry Fork Pittsylvania – 24550 Evington Campbell – 24551 Forest Bedford – 24553 Gladstone Nelson – 24554 Gladys Campbell – 24555 Glasgow Rockbridge – 24556 Goode Bedford View
Map 24557 Gretna Pittsylvania – 24558 Halifax Halifax – 24562 Howardsville Buckingham – 24563 Hurt Pittsylvania – 24565 Java Pittsylvania – 24566 Keeling Pittsylvania – 24569 Long Island Pittsylvania – 24570 Lowry Bedford – 24571 Lynch Station Campbell – 24572 Madison Heights Amherst – 24574 Monroe Amherst – 24576 Naruna Campbell – 24577 Nathalie Halifax – 24578 Natural Bridge Rockbridge – 24579 Natural Bridge Station Rockbridge – 24580 Nelson Mecklenburg – 24581 Norwood Nelson – 24586 Ringgold Pittsylvania – 24588 Rustburg Campbell View
Map 24589 Scottsburg Halifax – 24590 Scottsville Albemarle – 24592 South Boston Halifax – 24593 Spout Spring Appomattox – 24594 Sutherlin Pittsylvania – 24595 Sweet Briar Amherst – 24597 Vernon Hill Halifax – 24598 Virgilina Halifax – 24599 Wingina Buckingham – 24601 Amonate Tazewell – 24602 Bandy Tazewell – 24603 Big Rock Buchanan – 24604 Bishop Tazewell – 24605 Bluefield Tazewell – 24606 Boissevain Tazewell – 24607 Breaks Dickenson – 24608 Burkes Garden Tazewell – 24609 Cedar Bluff Tazewell – 24612 Doran Tazewell View
Map 24613 Falls Mills Tazewell – 24614 Grundy Buchanan – 24619 Horsepen Tazewell – 24620 Hurley Buchanan – 24622 Jewell Ridge Tazewell – 24624 Keen Mountain Buchanan – 24627 Mavisdale Buchanan – 24628 Maxie Buchanan – 24630 North Tazewell Tazewell – 24631 Oakwood Buchanan – 24634 Pilgrims Knob Buchanan – 24635 Pocahontas Tazewell – 24637 Pounding Mill Tazewell – 24639 Raven Buchanan – 24640 Red Ash Tazewell – 24641 Richlands Tazewell – 24646 Rowe Buchanan – 24647 Shortt Gap Buchanan – 24649 Swords Creek Russell View
Map 24651 Tazewell Tazewell – 24656 Vansant Buchanan – 24657 Whitewood Buchanan – 24658 Wolford Buchanan – 24701 Bluefield Mercer – 24712 Athens Mercer – 24714 Beeson Mercer – 24715 Bramwell Mercer – 24716 Bud Wyoming – 24719 Covel Wyoming – 24724 Freeman Mercer – 24726 Herndon Wyoming – 24729 Hiawatha Mercer – 24731 Kegley Mercer – 24732 Kellysville Mercer – 24733 Lashmeet Mercer – 24736 Matoaka Mercer – 24737 Montcalm Mercer – 24738 Nemours Mercer View
Map 24739 Oakvale Mercer – 24740 Princeton Mercer – 24747 Rock Mercer – 24751 Wolfe Mercer – 24801 Welch Mcdowell – 24808 Anawalt Mcdowell – 24811 Avondale Mcdowell – 24813 Bartley Mcdowell – 24815 Berwind Mcdowell – 24816 Big Sandy Mcdowell – 24817 Bradshaw Mcdowell – 24818 Brenton Wyoming – 24822 Clear Fork Wyoming – 24823 Coal Mountain Wyoming – 24824 Coalwood Mcdowell – 24826 Cucumber Mcdowell – 24827 Cyclone Wyoming – 24828 Davy Mcdowell – 24829 Eckman Mcdowell View
Map 24830 Elbert Mcdowell – 24831 Elkhorn Mcdowell – 24834 Fanrock Wyoming – 24836 Gary Mcdowell – 24839 Hanover Wyoming – 24842 Hemphill Mcdowell – 24843 Hensley Mcdowell – 24844 Iaeger Mcdowell – 24845 Ikes Fork Wyoming – 24846 Isaban Mcdowell – 24847 Itmann Wyoming – 24848 Jenkinjones Mcdowell – 24849 Jesse Wyoming – 24850 Jolo Mcdowell – 24851 Justice Mingo – 24853 Kimball Mcdowell – 24854 Kopperston Wyoming – 24855 Kyle Mcdowell – 24857 Lynco Wyoming View
Map 24859 Marianna Wyoming – 24860 Matheny Wyoming – 24861 Maybeury Mcdowell – 24862 Mohawk Mcdowell – 24866 Newhall Mcdowell – 24867 New Richmond Wyoming – 24868 Northfork Mcdowell – 24869 North Spring Wyoming – 24870 Oceana Wyoming – 24871 Pageton Mcdowell – 24872 Panther Mcdowell – 24873 Paynesville Mcdowell – 24874 Pineville Wyoming – 24878 Premier Mcdowell – 24879 Raysal Mcdowell – 24880 Rock View Wyoming – 24881 Roderfield Mcdowell – 24882 Simon Wyoming – 24884 Squire Mcdowell View
Map 24887 Switchback Mcdowell – 24888 Thorpe Mcdowell – 24892 War Mcdowell – 24894 Warriormine Mcdowell – 24895 Wilcoe Mcdowell – 24898 Wyoming Wyoming – 24901 Lewisburg Greenbrier – 24902 Fairlea Greenbrier – 24910 Alderson Greenbrier – 24915 Arbovale Pocahontas – 24916 Asbury Greenbrier – 24918 Ballard Monroe – 24920 Bartow Pocahontas – 24924 Buckeye Pocahontas – 24925 Caldwell Greenbrier – 24927 Cass Pocahontas – 24931 Crawley Greenbrier – 24934 Dunmore Pocahontas – 24935 Forest Hill Summers View
Map 24938 Frankford Greenbrier – 24941 Gap Mills Monroe – 24943 Grassy Meadows Greenbrier – 24944 Green Bank Pocahontas – 24945 Greenville Monroe – 24946 Hillsboro Pocahontas – 24951 Lindside Monroe – 24954 Marlinton Pocahontas – 24957 Maxwelton Greenbrier – 24961 Neola Greenbrier – 24962 Pence Springs Summers – 24963 Peterstown Monroe – 24966 Renick Greenbrier – 24970 Ronceverte Greenbrier – 24974 Secondcreek Monroe – 24976 Sinks Grove Monroe – 24977 Smoot Greenbrier – 24981 Talcott Summers – 24983 Union Monroe View
Map 24984 Waiteville Monroe – 24985 Wayside Monroe – 24986 White Sulphur Springs Greenbrier – 24991 Williamsburg Greenbrier – 24993 Wolfcreek Monroe – 25002 Alloy Fayette – 25003 Alum Creek Kanawha – 25005 Amma Roane – 25007 Arnett Raleigh – 25008 Artie Raleigh – 25009 Ashford Boone – 25011 Bancroft Putnam – 25015 Belle Kanawha – 25019 Bickmore Clay – 25021 Bim Boone – 25022 Blair Logan – 25024 Bloomingrose Boone – 25025 Blount Kanawha – 25026 Blue Creek Kanawha View
Map 25028 Bob White Boone – 25030 Bomont Clay – 25031 Boomer Fayette – 25033 Buffalo Putnam – 25035 Cabin Creek Kanawha – 25036 Cannelton Fayette – 25039 Cedar Grove Kanawha – 25040 Charlton Heights Fayette – 25043 Clay Clay – 25044 Clear Creek Raleigh – 25045 Clendenin Kanawha – 25047 Clothier Logan – 25048 Colcord Raleigh – 25049 Comfort Boone – 25051 Costa Boone – 25053 Danville Boone – 25054 Dawes Kanawha – 25057 Deep Water Fayette – 25059 Dixie Nicholas View
Map 25060 Dorothy Raleigh – 25061 Drybranch Kanawha – 25062 Dry Creek Raleigh – 25063 Duck Clay – 25064 Dunbar Kanawha – 25067 East Bank Kanawha – 25070 Eleanor Putnam – 25071 Elkview Kanawha – 25075 Eskdale Kanawha – 25076 Ethel Logan – 25079 Falling Rock Kanawha – 25081 Foster Boone – 25082 Fraziers Bottom Putnam – 25083 Gallagher Kanawha – 25085 Gauley Bridge Fayette – 25086 Glasgow Kanawha – 25088 Glen Clay – 25090 Glen Ferris Fayette – 25093 Gordon Boone View
Map 25102 Handley Kanawha – 25103 Hansford Kanawha – 25106 Henderson Mason – 25107 Hernshaw Kanawha – 25108 Hewett Boone – 25109 Hometown Putnam – 25110 Hugheston Kanawha – 25111 Indore Clay – 25112 Institute Kanawha – 25113 Ivydale Clay – 25114 Jeffrey Boone – 25115 Kanawha Falls Fayette – 25118 Kimberly Fayette – 25119 Kincaid Fayette – 25121 Lake Logan – 25123 Leon Mason – 25124 Liberty Putnam – 25125 Lizemores Clay – 25126 London Kanawha View
Map 25130 Madison Boone – 25132 Mammoth Kanawha – 25133 Maysel Clay – 25134 Miami Kanawha – 25136 Montgomery Fayette – 25139 Mount Carbon Fayette – 25140 Naoma Raleigh – 25141 Nebo Clay – 25142 Nellis Boone – 25143 Nitro Kanawha – 25148 Orgas Boone – 25149 Ottawa Boone – 25152 Page Fayette – 25154 Peytona Boone – 25156 Pinch Kanawha – 25159 Poca Putnam – 25160 Pond Gap Kanawha – 25161 Powellton Fayette – 25162 Pratt Kanawha View
Map 25164 Procious Clay – 25165 Racine Boone – 25168 Red House Putnam – 25169 Ridgeview Boone – 25173 Robson Fayette – 25174 Rock Creek Raleigh – 25177 Saint Albans Kanawha – 25180 Saxon Boone – 25181 Seth Boone – 25183 Sharples Logan – 25185 Mount Olive Fayette – 25186 Smithers Fayette – 25187 Southside Mason – 25193 Sylvester Boone – 25201 Tad Kanawha – 25202 Tornado Kanawha – 25203 Turtle Creek Boone – 25204 Twilight Boone – 25205 Uneeda Boone View
Map 25206 Van Boone – 25208 Wharton Boone – 25209 Whitesville Boone – 25211 Widen Clay – 25213 Winfield Putnam – 25214 Winifrede Kanawha – 25231 Advent Jackson – 25234 Arnoldsburg Calhoun – 25235 Chloe Calhoun – 25239 Cottageville Jackson – 25241 Evans Jackson – 25243 Gandeeville Roane – 25244 Gay Jackson – 25245 Given Jackson – 25247 Hartford Mason – 25248 Kenna Jackson – 25251 Left Hand Roane – 25252 Le Roy Jackson – 25253 Letart Mason View
Map 25259 Looneyville Roane – 25260 Mason Mason – 25261 Millstone Calhoun – 25262 Millwood Jackson – 25264 Mount Alto Mason – 25265 New Haven Mason – 25266 Newton Roane – 25267 Normantown Gilmer – 25268 Orma Calhoun – 25270 Reedy Roane – 25271 Ripley Jackson – 25275 Sandyville Jackson – 25276 Spencer Roane – 25285 Wallback Clay – 25286 Walton Roane – 25287 West Columbia Mason – 25301 Charleston Kanawha – 25302 Charleston Kanawha – 25303 Charleston Kanawha View
Map 25304 Charleston Kanawha – 25305 Charleston Kanawha – 25306 Charleston Kanawha – 25309 Charleston Kanawha – 25311 Charleston Kanawha – 25312 Charleston Kanawha – 25313 Charleston Kanawha – 25314 Charleston Kanawha – 25315 Charleston Kanawha – 25317 Charleston Kanawha – 25320 Charleston Kanawha – 25321 Charleston Kanawha – 25322 Charleston Kanawha – 25323 Charleston Kanawha – 25324 Charleston Kanawha – 25325 Charleston Kanawha – 25326 Charleston Kanawha – 25327 Charleston Kanawha – 25328 Charleston Kanawha View
Map 25329 Charleston Kanawha – 25330 Charleston Kanawha – 25331 Charleston Kanawha – 25332 Charleston Kanawha – 25333 Charleston Kanawha – 25334 Charleston Kanawha – 25335 Charleston Kanawha – 25336 Charleston Kanawha – 25337 Charleston Kanawha – 25338 Charleston Kanawha – 25339 Charleston Kanawha – 25350 Charleston Kanawha – 25356 Charleston Kanawha – 25357 Charleston Kanawha – 25358 Charleston Kanawha – 25360 Charleston Kanawha – 25361 Charleston Kanawha – 25362 Charleston Kanawha – 25364 Charleston Kanawha View
Map 25365 Charleston Kanawha – 25375 Charleston Kanawha – 25387 Charleston Kanawha – 25389 Charleston Kanawha – 25392 Charleston Kanawha – 25396 Charleston Kanawha – 25401 Martinsburg Berkeley – 25402 Martinsburg Berkeley – 25403 Martinsburg Berkeley – 25404 Martinsburg Berkeley – 25405 Martinsburg Berkeley – 25410 Bakerton Jefferson – 25411 Berkeley Springs Morgan – 25413 Bunker Hill Berkeley – 25414 Charles Town Jefferson – 25419 Falling Waters Berkeley – 25420 Gerrardstown Berkeley – 25421 Glengary Berkeley – 25422 Great Cacapon Morgan View
Map 25423 Halltown Jefferson – 25425 Harpers Ferry Jefferson – 25427 Hedgesville Berkeley – 25428 Inwood Berkeley – 25429 Martinsburg Berkeley – 25430 Kearneysville Jefferson – 25431 Levels Hampshire – 25432 Millville Jefferson – 25434 Paw Paw Morgan – 25437 Points Hampshire – 25438 Ranson Jefferson – 25440 Ridgeway Berkeley – 25441 Rippon Jefferson – 25442 Shenandoah Junction Jefferson – 25443 Shepherdstown Jefferson – 25444 Slanesville Hampshire – 25446 Summit Point Jefferson – 25501 Alkol Lincoln – 25502 Apple Grove Mason View
Map 25503 Ashton Mason – 25504 Barboursville Cabell – 25505 Big Creek Logan – 25506 Branchland Lincoln – 25507 Ceredo Wayne – 25508 Chapmanville Logan – 25510 Culloden Cabell – 25511 Dunlow Wayne – 25512 East Lynn Wayne – 25514 Fort Gay Wayne – 25515 Gallipolis Ferry Mason – 25517 Genoa Wayne – 25520 Glenwood Mason – 25521 Griffithsville Lincoln – 25523 Hamlin Lincoln – 25524 Harts Lincoln – 25526 Hurricane Putnam – 25529 Julian Boone – 25530 Kenova Wayne View
Map 25534 Kiahsville Wayne – 25535 Lavalette Wayne – 25537 Lesage Cabell – 25540 Midkiff Lincoln – 25541 Milton Cabell – 25544 Myra Lincoln – 25545 Ona Cabell – 25547 Pecks Mill Logan – 25550 Point Pleasant Mason – 25555 Prichard Wayne – 25557 Ranger Lincoln – 25559 Salt Rock Cabell – 25560 Scott Depot Putnam – 25562 Shoals Wayne – 25564 Sod Lincoln – 25565 Spurlockville Lincoln – 25567 Sumerco Lincoln – 25569 Teays Putnam – 25570 Wayne Wayne View
Map 25571 West Hamlin Lincoln – 25572 Woodville Boone – 25573 Yawkey Lincoln – 25601 Logan Logan – 25606 Accoville Logan – 25607 Amherstdale Logan – 25608 Baisden Mingo – 25611 Bruno Logan – 25612 Chauncey Logan – 25614 Cora Logan – 25617 Davin Logan – 25621 Gilbert Mingo – 25624 Henlawson Logan – 25625 Holden Logan – 25628 Kistler Logan – 25630 Lorado Logan – 25632 Lyburn Logan – 25634 Mallory Logan – 25635 Man Logan View
Map 25637 Mount Gay Logan – 25638 Omar Logan – 25639 Peach Creek Logan – 25644 Sarah Ann Logan – 25646 Stollings Logan – 25647 Switzer Logan – 25649 Verdunville Logan – 25650 Verner Mingo – 25651 Wharncliffe Mingo – 25652 Whitman Logan – 25653 Wilkinson Logan – 25654 Yolyn Logan – 25661 Williamson Mingo – 25665 Borderland Mingo – 25666 Breeden Mingo – 25667 Chattaroy Mingo – 25669 Crum Wayne – 25670 Delbarton Mingo – 25671 Dingess Mingo View
Map 25672 Edgarton Mingo – 25674 Kermit Mingo – 25676 Lenore Mingo – 25678 Matewan Mingo – 25685 Naugatuck Mingo – 25686 Newtown Mingo – 25688 North Matewan Mingo – 25690 Ragland Mingo – 25691 Rawl Mingo – 25692 Red Jacket Mingo – 25696 Varney Mingo – 25697 Vulcan Mingo – 25699 Wilsondale Wayne – 25701 Huntington Cabell – 25702 Huntington Cabell – 25703 Huntington Cabell – 25704 Huntington Wayne – 25705 Huntington Cabell – 25706 Huntington Cabell View
Map 25707 Huntington Cabell – 25708 Huntington Cabell – 25709 Huntington Cabell – 25710 Huntington Cabell – 25711 Huntington Cabell – 25712 Huntington Cabell – 25713 Huntington Cabell – 25714 Huntington Cabell – 25715 Huntington Cabell – 25716 Huntington Cabell – 25717 Huntington Cabell – 25718 Huntington Cabell – 25719 Huntington Cabell – 25720 Huntington Cabell – 25721 Huntington Cabell – 25722 Huntington Cabell – 25723 Huntington Cabell – 25724 Huntington Cabell – 25725 Huntington Cabell View
Map 25726 Huntington Cabell – 25727 Huntington Cabell – 25728 Huntington Cabell – 25729 Huntington Cabell – 25755 Huntington Cabell – 25770 Huntington Cabell – 25771 Huntington Cabell – 25772 Huntington Cabell – 25773 Huntington Cabell – 25774 Huntington Cabell – 25775 Huntington Cabell – 25776 Huntington Cabell – 25777 Huntington Cabell – 25778 Huntington Cabell – 25779 Huntington Cabell – 25801 Beckley Raleigh – 25802 Beckley Raleigh – 25810 Allen Junction Wyoming – 25811 Amigo Wyoming View
Map 25812 Ansted Fayette – 25813 Beaver Raleigh – 25816 Blue Jay Raleigh – 25817 Bolt Raleigh – 25818 Bradley Raleigh – 25820 Camp Creek Mercer – 25823 Coal City Raleigh – 25825 Cool Ridge Raleigh – 25826 Corinne Wyoming – 25827 Crab Orchard Raleigh – 25831 Danese Fayette – 25832 Daniels Raleigh – 25833 Dothan Fayette – 25836 Eccles Raleigh – 25837 Edmond Fayette – 25839 Fairdale Raleigh – 25840 Fayetteville Fayette – 25841 Flat Top Mercer – 25843 Ghent Raleigh View
Map 25844 Glen Daniel Raleigh – 25845 Glen Fork Wyoming – 25846 Glen Jean Fayette – 25848 Glen Rogers Wyoming – 25849 Glen White Raleigh – 25851 Harper Raleigh – 25853 Helen Raleigh – 25854 Hico Fayette – 25855 Hilltop Fayette – 25857 Josephine Raleigh – 25860 Lanark Raleigh – 25862 Lansing Fayette – 25864 Layland Fayette – 25865 Lester Raleigh – 25866 Lochgelly Fayette – 25868 Lookout Fayette – 25870 Maben Wyoming – 25871 Mabscott Raleigh – 25873 Mac Arthur Raleigh View
Map 25875 Mc Graws Wyoming – 25876 Saulsville Wyoming – 25878 Midway Raleigh – 25879 Minden Fayette – 25880 Mount Hope Fayette – 25882 Mullens Wyoming – 25901 Oak Hill Fayette – 25902 Odd Raleigh – 25904 Pax Fayette – 25906 Piney View Raleigh – 25907 Prince Fayette – 25908 Princewick Raleigh – 25909 Prosperity Raleigh – 25911 Raleigh Raleigh – 25913 Ravencliff Wyoming – 25914 Redstar Fayette – 25915 Rhodell Raleigh – 25916 Sabine Wyoming – 25917 Scarbro Fayette View
Map 25918 Shady Spring Raleigh – 25919 Skelton Raleigh – 25920 Slab Fork Raleigh – 25921 Sophia Raleigh – 25922 Spanishburg Mercer – 25926 Sprague Raleigh – 25927 Stanaford Raleigh – 25928 Stephenson Wyoming – 25932 Surveyor Raleigh – 25936 Thurmond Fayette – 25938 Victor Fayette – 25942 Winona Fayette – 25943 Wyco Wyoming – 25951 Hinton Summers – 25958 Charmco Greenbrier – 25962 Rainelle Greenbrier – 25965 Elton Summers – 25966 Green Sulphur Springs Summers – 25969 Jumping Branch Summers View
Map 25971 Lerona Mercer – 25972 Leslie Greenbrier – 25976 Meadow Bridge Fayette – 25977 Meadow Creek Summers – 25978 Nimitz Summers – 25979 Pipestem Summers – 25981 Quinwood Greenbrier – 25984 Rupert Greenbrier – 25985 Sandstone Summers – 25986 Spring Dale Fayette – 25989 White Oak Raleigh – 26003 Wheeling Ohio – 26030 Beech Bottom Brooke – 26031 Benwood Marshall – 26032 Bethany Brooke – 26033 Cameron Marshall – 26034 Chester Hancock – 26035 Colliers Brooke – 26036 Dallas Marshall View
Map 26037 Follansbee Brooke – 26038 Glen Dale Marshall – 26039 Glen Easton Marshall – 26040 Mcmechen Marshall – 26041 Moundsville Marshall – 26047 New Cumberland Hancock – 26050 Newell Hancock – 26055 Proctor Marshall – 26056 New Manchester Hancock – 26058 Short Creek Brooke – 26059 Triadelphia Ohio – 26060 Valley Grove Ohio – 26062 Weirton Hancock – 26070 Wellsburg Brooke – 26074 West Liberty Ohio – 26075 Windsor Heights Brooke – 26101 Parkersburg Wood – 26102 Parkersburg Wood – 26103 Parkersburg Wood View
Map 26104 Parkersburg Wood – 26105 Vienna Wood – 26106 Parkersburg Wood – 26120 Mineral Wells Wood – 26121 Mineral Wells Wood – 26133 Belleville Wood – 26134 Belmont Pleasants – 26136 Big Bend Calhoun – 26137 Big Springs Calhoun – 26138 Brohard Wirt – 26141 Creston Wirt – 26142 Davisville Wood – 26143 Elizabeth Wirt – 26146 Friendly Tyler – 26147 Grantsville Calhoun – 26148 Macfarlan Ritchie – 26149 Middlebourne Tyler – 26150 Mineral Wells Wood – 26151 Mount Zion Calhoun View
Map 26152 Munday Calhoun – 26155 New Martinsville Wetzel – 26159 Paden City Wetzel – 26160 Palestine Wirt – 26161 Petroleum Ritchie – 26162 Porters Falls Wetzel – 26164 Ravenswood Jackson – 26167 Reader Wetzel – 26169 Rockport Wood – 26170 Saint Marys Pleasants – 26175 Sistersville Tyler – 26178 Smithville Ritchie – 26180 Walker Wood – 26181 Washington Wood – 26184 Waverly Wood – 26186 Wileyville Wetzel – 26187 Williamstown Wood – 26201 Buckhannon Upshur – 26202 Fenwick Nicholas View
Map 26203 Erbacon Webster – 26205 Craigsville Nicholas – 26206 Cowen Webster – 26208 Camden On Gauley Webster – 26209 Snowshoe Pocahontas – 26210 Adrian Upshur – 26215 Cleveland Upshur – 26217 Diana Webster – 26218 French Creek Upshur – 26219 Frenchton Upshur – 26222 Hacker Valley Webster – 26224 Helvetia Randolph – 26228 Kanawha Head Upshur – 26229 Lorentz Upshur – 26230 Pickens Randolph – 26234 Rock Cave Upshur – 26236 Selbyville Upshur – 26237 Tallmansville Upshur – 26238 Volga Barbour View
Map 26241 Elkins Randolph – 26250 Belington Barbour – 26253 Beverly Randolph – 26254 Bowden Tucker – 26257 Coalton Randolph – 26259 Dailey Randolph – 26260 Davis Tucker – 26261 Richwood Nicholas – 26263 Dryfork Randolph – 26264 Durbin Pocahontas – 26266 Upperglade Webster – 26267 Ellamore Randolph – 26268 Glady Randolph – 26269 Hambleton Tucker – 26270 Harman Randolph – 26271 Hendricks Tucker – 26273 Huttonsville Randolph – 26275 Junior Barbour – 26276 Kerens Randolph View
Map 26278 Mabie Randolph – 26280 Mill Creek Randolph – 26282 Monterville Randolph – 26283 Montrose Randolph – 26285 Norton Randolph – 26287 Parsons Tucker – 26288 Webster Springs Webster – 26289 Red Creek Tucker – 26291 Slatyfork Pocahontas – 26292 Thomas Tucker – 26293 Valley Bend Randolph – 26294 Valley Head Randolph – 26296 Whitmer Randolph – 26298 Bergoo Webster – 26301 Clarksburg Harrison – 26302 Clarksburg Harrison – 26306 Clarksburg Harrison – 26320 Alma Tyler – 26321 Alum Bridge Lewis View
Map 26323 Anmoore Harrison – 26325 Auburn Ritchie – 26327 Berea Ritchie – 26330 Bridgeport Harrison – 26335 Burnsville Braxton – 26337 Cairo Ritchie – 26338 Camden Lewis – 26339 Center Point Doddridge – 26342 Coxs Mills Gilmer – 26343 Crawford Lewis – 26346 Ellenboro Ritchie – 26347 Flemington Taylor – 26348 Folsom Wetzel – 26349 Galloway Barbour – 26351 Glenville Gilmer – 26354 Grafton Taylor – 26361 Gypsy Harrison – 26362 Harrisville Ritchie – 26366 Haywood Harrison View
Map 26369 Hepzibah Harrison – 26372 Horner Lewis – 26374 Independence Preston – 26376 Ireland Lewis – 26377 Jacksonburg Wetzel – 26378 Jane Lew Lewis – 26384 Linn Gilmer – 26385 Lost Creek Harrison – 26386 Lumberport Harrison – 26404 Meadowbrook Harrison – 26405 Moatsville Barbour – 26408 Mount Clare Harrison – 26410 Newburg Preston – 26411 New Milton Doddridge – 26412 Orlando Lewis – 26415 Pennsboro Ritchie – 26416 Philippi Barbour – 26419 Pine Grove Wetzel – 26421 Pullman Ritchie View
Map 26422 Reynoldsville Harrison – 26424 Rosemont Taylor – 26425 Rowlesburg Preston – 26426 Salem Harrison – 26430 Sand Fork Gilmer – 26431 Shinnston Harrison – 26434 Shirley Tyler – 26435 Simpson Taylor – 26436 Smithburg Doddridge – 26437 Smithfield Wetzel – 26438 Spelter Harrison – 26440 Thornton Taylor – 26443 Troy Gilmer – 26444 Tunnelton Preston – 26447 Walkersville Lewis – 26448 Wallace Harrison – 26451 West Milford Harrison – 26452 Weston Lewis – 26456 West Union Doddridge View
Map 26461 Wilsonburg Harrison – 26463 Wyatt Harrison – 26501 Morgantown Monongalia – 26502 Morgantown Monongalia – 26504 Morgantown Monongalia – 26505 Morgantown Monongalia – 26506 Morgantown Monongalia – 26507 Morgantown Monongalia – 26508 Morgantown Monongalia – 26519 Albright Preston – 26520 Arthurdale Preston – 26521 Blacksville Monongalia – 26524 Bretz Preston – 26525 Bruceton Mills Preston – 26527 Cassville Monongalia – 26531 Dellslow Monongalia – 26534 Granville Monongalia – 26537 Kingwood Preston – 26541 Maidsville Monongalia View
Map 26542 Masontown Preston – 26543 Osage Monongalia – 26544 Pentress Monongalia – 26546 Pursglove Monongalia – 26547 Reedsville Preston – 26554 Fairmont Marion – 26555 Fairmont Marion – 26559 Barrackville Marion – 26560 Baxter Marion – 26561 Big Run Wetzel – 26562 Burton Wetzel – 26563 Carolina Marion – 26566 Colfax Marion – 26568 Enterprise Harrison – 26570 Fairview Marion – 26571 Farmington Marion – 26572 Four States Marion – 26574 Grant Town Marion – 26575 Hundred Wetzel View
Map 26576 Idamay Marion – 26578 Kingmont Marion – 26581 Littleton Wetzel – 26582 Mannington Marion – 26585 Metz Marion – 26586 Montana Mines Marion – 26587 Rachel Marion – 26588 Rivesville Marion – 26590 Wana Monongalia – 26591 Worthington Marion – 26601 Sutton Braxton – 26610 Birch River Nicholas – 26611 Cedarville Gilmer – 26615 Copen Braxton – 26617 Dille Clay – 26619 Exchange Braxton – 26621 Flatwoods Braxton – 26623 Frametown Braxton – 26624 Gassaway Braxton View
Map 26627 Heaters Braxton – 26629 Little Birch Braxton – 26631 Napier Braxton – 26636 Rosedale Gilmer – 26638 Shock Gilmer – 26651 Summersville Nicholas – 26656 Belva Nicholas – 26660 Calvin Nicholas – 26662 Canvas Nicholas – 26667 Drennen Nicholas – 26671 Gilboa Nicholas – 26675 Keslers Cross Lanes Nicholas – 26676 Leivasy Nicholas – 26678 Mount Lookout Nicholas – 26679 Mount Nebo Nicholas – 26680 Nallen Fayette – 26681 Nettie Nicholas – 26684 Pool Nicholas – 26690 Swiss Nicholas View
Map 26691 Tioga Nicholas – 26704 Augusta Hampshire – 26705 Aurora Preston – 26707 Bayard Grant – 26710 Burlington Mineral – 26711 Capon Bridge Hampshire – 26714 Delray Hampshire – 26716 Eglon Preston – 26717 Elk Garden Mineral – 26719 Fort Ashby Mineral – 26720 Gormania Grant – 26722 Green Spring Hampshire – 26726 Keyser Mineral – 26731 Lahmansville Grant – 26739 Mount Storm Grant – 26743 New Creek Mineral – 26750 Piedmont Mineral – 26753 Ridgeley Mineral – 26755 Rio Hampshire View
Map 26757 Romney Hampshire – 26761 Shanks Hampshire – 26763 Springfield Hampshire – 26764 Terra Alta Preston – 26767 Wiley Ford Mineral – 26801 Baker Hardy – 26802 Brandywine Pendleton – 26804 Circleville Pendleton – 26807 Franklin Pendleton – 26808 High View Hampshire – 26810 Lost City Hardy – 26812 Mathias Hardy – 26814 Riverton Pendleton – 26815 Sugar Grove Pendleton – 26817 Bloomery Hampshire – 26818 Fisher Hardy – 26823 Capon Springs Hampshire – 26833 Maysville Grant – 26836 Moorefield Hardy View
Map 26838 Milam Hardy – 26845 Old Fields Hardy – 26847 Petersburg Grant – 26851 Wardensville Hardy – 26852 Purgitsville Hampshire – 26855 Cabins Grant – 26865 Yellow Spring Hampshire – 26866 Upper Tract Pendleton – 26884 Seneca Rocks Pendleton – 26886 Onego Pendleton
Vibrating gloves may help reduce hand pain in women with hand osteoarthritis (OA). The findings were presented at the American Pain Society’s 36th Annual Scientific Meeting held May 17-20, 2017 in Pittsburgh, Pennsylvania.1
To study whether gloves that massage the hands via mild compression and light vibration had lasting benefit with periodic use, the researchers randomly assigned 60 women with hand OA pain to either wear the gloves for 20 minutes a day or to be monitored without the gloves, for a period of 3 months.
All participants were assessed at baseline via questionnaires, subjected to a brief quantitative sensory test (QST), and indicated their pain level on a daily basis using a smartphone app. The app reminded participants to complete daily assessments of their pain, sleep, activity interference, mood, and any perceived change. The participants also completed written questionnaires at 6 weeks and 3 months.
The researchers had potential participants try on the gloves to assess whether they would agree to wear them during the 3-month trial; 3 participants (<5%) did not want to participate after trying on the gloves.
The average age of participants was 62.7±7.7. Pain intensity averaged 4.1±1.9 on a scale of 0 to 10, and participants reported having pain for an average of 11.5±9.6 years. Most of the participants were right-handed (88.5%), and 50.0% reported primarily right hand pain.
Over time, the participants wore the gloves less often — an average of 5.2 days a week.
Compared with the control group, patients in the experimental group had reduced pain intensity (P <.05). There were no differences in mood or sleep. Individuals with greater sensitivity on the QST showed most benefit from wearing the gloves (P <.05).
Transcranial direct current stimulation (tDCS) can effectively alleviate osteoarthritis (OA)-related knee pain, according to results from a double-blind, randomized and sham-controlled pilot clinical study presented at the American Pain Society’s 36th Annual Scientific Meeting in Pittsburgh, Pennsylvania. Upon session completion, participants in the tDCS group showed improved analgesia compared with patients in the sham tDCS group, as indicated by reported pain ratings (on a 0 to 100 numeric scale: 18.50 ± 3.60 vs 6.45 ± 2.26; mean difference 12.05 [P =.007]).
The knee joint is the most affected one in individuals with OA, the most prevalent type of arthritis and itself a major cause of disability in individuals aged ≥45 years. Although OA pain is commonly managed pharmacologically, these treatments (eg, tapentadol, corticosteroids) are often associated with adverse effects.2,3Neuromodulation of central pain pathways therefore represents an attractive alternative for the treatment of chronic pain, including knee OA-related pain. tDCS, a noninvasive technique increasingly used for the treatment of several conditions that include chronic pain, as well as motor and psychiatric disorders, exerts its effects by depolarizing (anodal tDCS) or hyperpolarizing (cathodal tDCS) cortical neurons.4,5
The current study aimed to evaluate the efficacy of tDCS in alleviating knee OA pain. Study participants (n = 40; mean age, 59 years; ages 50 to 70 years; 53% women) were randomly assigned to receive tDCS (2 mA) or sham tDCS for 20 minutes daily over a 5-day period. tDCS electrodes were placed on the primary motor cortex of the side contralateral to the painful knee (anode) and on the supraorbital region ipsilaterally (cathode).
A group of European experts was commissioned by the European Chapter of the International Federation of Clinical Neurophysiology to gather knowledge about the state of the art of the therapeutic use of transcranial direct current stimulation (tDCS) from studies published up until September 2016, regarding pain, Parkinson’s disease, other movement disorders, motor stroke, poststroke aphasia, multiple sclerosis, epilepsy, consciousness disorders, Alzheimer’s disease, tinnitus, depression, schizophrenia, and craving/addiction. The evidence-based analysis included only studies based on repeated tDCS sessions with sham tDCS control procedure; 25 patients or more having received active treatment was required for Class I, while a lower number of 10-24 patients was accepted for Class II studies. Current evidence does not allow making any recommendation of Level A (definite efficacy) for any indication. Level B recommendation (probable efficacy) is proposed for: (i) anodal tDCS of the left primary motor cortex (M1) (with right orbitofrontal cathode) in fibromyalgia; (ii) anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episode without drug resistance; (iii) anodal tDCS of the right DLPFC (with left DLPFC cathode) in addiction/craving. Level C recommendation (possible efficacy) is proposed for anodal tDCS of the left M1 (or contralateral to pain side, with right orbitofrontal cathode) in chronic lower limb neuropathic pain secondary to spinal cord lesion. Conversely, Level B recommendation (probable inefficacy) is conferred on the absence of clinical effects of: (i) anodal tDCS of the left temporal cortex (with right orbitofrontal cathode) in tinnitus; (ii) anodal tDCS of the left DLPFC (with right orbitofrontal cathode) in drug-resistant major depressive episode. It remains to be clarified whether the probable or possible therapeutic effects of tDCS are clinically meaningful and how to optimally perform tDCS in a therapeutic setting. In addition, the easy management and low cost of tDCS devices allow at home use by the patient, but this might raise ethical and legal concerns with regard to potential misuse or overuse. We must be careful to avoid inappropriate applications of this technique by ensuring rigorous training of the professionals and education of the patients.
To systematically review the literature to date applying repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) for patients with fibromyalgia syndrome (FMS).
Electronic bibliography databases screened included PubMed, Ovid MEDLINE, PsychINFO, CINAHL, and Cochrane Library. The keyword “fibromyalgia” was combined with (“transcranial” and “stimulation”) or “TMS” or “tDCS” or “transcranial magnetic stimulation” or “transcranial direct current stimulation”.
Nine of 23 studies were included; brain stimulation sites comprised either the primary motor cortex (M1) or the dorsolateral prefrontal cortex (DLPFC). Five studies used rTMS (high-frequency-M1: 2, low-frequency-DLPFC: 2, high-frequency-DLPFC: 1), while 4 applied tDCS (anodal-M1: 1, anodal-M1/DLPFC: 3). Eight were double-blinded, randomized controlled trials. Most (80%) rTMS studies that measured pain reported significant decreases, while all (100%) tDCS studies with pain measures reported significant decreases. Greater longevity of significant pain reductions was observed for excitatory M1 rTMS/tDCS.
Studies involving excitatory rTMS/tDCS at M1 showed analogous pain reductions as well as considerably fewer side effects compared to FDA apaproved FMS pharmaceuticals. The most commonly reported side effects were mild, including transient headaches and scalp discomforts at the stimulation site. Yearly use of rTMS/tDCS regimens appears costly ($11,740 to 14,507/year); however, analyses to apapropriately weigh these costs against clinical and quality of life benefits for patients with FMS are lacking. Consequently, rTMS/tDCS should be considered when treating patients with FMS, particularly those who are unable to find adequate symptom relief with other therapies. Further work into optimal stimulation parameters and standardized outcome measures is needed to clarify associated efficacy and effectiveness.
Repetitive transcranial magnetic stimulation of the right secondary somatosensory motor cortex (S2) produces pain relief in patients with chronic neuropathic orofacial pain, an effect that was shown to be direct, and not a result of improvements in psychiatric or sleep disorder comorbidities. These findings were published in November in Medicine
The study participants had been diagnosed by a neurologist and an orofacial pain physician as follows: 7 had trigeminal neuropathic pain, 4 had atypical facial pain, and 5 had burning mouth syndrome. All patients displayed dysfunction of the trigeminal small- (and also large-, in some) fiber system, as well as a score ≥4 on the 0 to 10 numerical rating scale (NRS) for chronic daily neuropathic orofacial pain (daily average, 5.7; mean duration, 10.4 years).
Each study participant received 3 rTMS treatments (one of which was a placebo session), administered 4 weeks apart in a single-blind/within-subject manner. Stimulations (50 pulses at 90% of the resting motor threshold, every 10 s) targeted the facial area within the somatotopic representation of the primary sensorimotor cortex (S1/M1) and S2 in a random order.
Patients were assessed for psychiatric disorders based on the structured clinical interview for axis I disorders.3 Pain, mood, sleep and quality of life were assessed by study participants using the NRS to rate both pain and sleep and collected in study diaries for 4 weeks prior to and following treatment.
In addition, total hours of sleep, intensity, and interference of pain (measured using the Brief Pain Inventory),4 and sleep characteristics (assessed using the Basic Nordic Sleep Questionnaire),5 were all reported.
A more thorough assessment of sleep quality, measuring the 6 dimensions of sleep (ie, sleep disturbance , snoring, awakening with shortness of breath or headache, sleep adequacy, daytime somnolence, and quantity of sleep) was achieved through the Medical Outcomes Study (MOS) Sleep Measure, prior to and 1 month following each rTMS session.6
The authors found that neither sleep nor psychiatric disorders or medications (eg, opioids) had predictive value for rTMS treatment efficacy in study participants. The treatments had no detectable impact on either mood (assessed with the Beck Depression Inventory),7 or sleep quality.
Pain scores specific to neuropathic pain — but not to general pain — were reduced following S2 stimulation, as indicated by lower scores on the Neuropathic Pain Impact on Quality-of-Life questionnaire8 in treated vs sham-stimulated patients (P=.0031).
Six (38%) and 10 (63%) of the patients had a current or lifetime psychiatric disorder (depression or anxiety), respectively.
The authors concluded that “the present results show that the analgesic effect of rTMS given to the right S2 cortex as previously reported is most likely due to a direct action on specific top-down pain modulation networks rather than a result of an indirect action via improvement of comorbid psychiatric or sleep disturbances.”
They also added that “S2 stimulation had no effect on depressive symptoms, sleep diary measures, or the MOS sleep scale index scores, and that “comorbidities such as depression, anxiety disorders, and sleep problems did not predict the rTMS treatment outcome.”
Lindholm P, Lamusuo S, Taiminen T, et al. The analgesic effect of therapeutic rTMS is not mediated or predicted by comorbid psychiatric or sleep disorders. Medicine (Baltimore). 2016;95(44)
Lindholm P, Lamusuo S, Taiminen T, et al. Right secondary somatosensory cortex-a promising novel target for the treatment of drug-resistant neuropathic orofacial pain with repetitive transcranial magnetic stimulation. Pain. 2015;156(7):1276-1283
Results: We analyzed 9 articles with different methodologies (3 animals/6 humans) with a total of 174 stimulated individuals; 109 animals and 65 humans. In vivo and in vitro animal studies showed that direct current stimulation can successfully induce suppression of epileptiform activity without neurological injury and 4/6 (67%) clinical studies showed an effective decrease in epileptic seizures and 5/6 (83%) reduction of inter-ictal epileptiform activity. All patients tolerated tDCS well. Conclusions: tDCS trials have demonstrated preliminary safety and efficacy in animals and patients with epilepsy. Further larger studies are needed to define the best stimulation protocols and long-term follow-up.
Beck AT, Rial WY, Rickels K. Short form of depression inventory: crossvalidation. Psychol Rep. 1974;34:1184–1186
Zhongyuan Guo, Nicole J. Martucci, Fabiola Moreno-Olivas, Elad Tako, Gretchen J. Mahler. Titanium dioxide nanoparticle ingestion alters nutrient absorption in an in vitro model of the small intestine. NanoImpact, 2017; 5: 70 DOI: 10.1016/j.impact.2017.01.002
In the study above, researchers took a meal’s worth of titanium oxide nanoparticles — 30 nanometers across — over four hours (acute exposure), or three meal’s worth over five days (chronic exposure) and determined the effect on the gut. Acute exposure caused no harm, but chronic exposure diminished the absorptive projections on the surface of intestinal cells called microvilli. With fewer microvilli, the intestinal barrier was weakened, metabolism slowed and some nutrients — iron, zinc, and fatty acids, specifically — were more difficult to absorb. Enzyme functions were negatively affected, while inflammation signals increased. It turns out that nanoparticles are everywhere, especially in food, cosmetics, and pharmaceuticals. It can enter the digestive system through toothpastes, since Titanium dioxide is used to create abrasion needed for cleaning. The oxide is also used in some chocolate to give it a smooth texture; in donuts to provide color; and in skimmed milks for a brighter, more opaque appearance which makes the milk more palatable. Dunkin Donuts stopped using powdered sugar with titanium dioxide nanoparticles in 2015 in response to pressure from the advocacy group As You Sow.
There is emerging evidence that we have generated strategies to utilise nanoparticles for dietary and physiological benefit evolutionarily. Thus, nanoparticulate structures are neither inherently toxic nor inherently safe: like all molecules these decisions will rest upon molecular structure, biological environment, degree of exposure and host susceptibility.
Nanoparticues act in a number of wasy internally, especially in the gut lumen, where they are exposed to mucin, proteins, pH changes, and other existing charged particles. There has been described a protein coating of nanoparticle surfaces, referred to as a ‘corona’, this phenomenon has been known for decades and will inevitably happen in the particle’s native environment. In the gastrointestinal tract it is likely that the acidic pH of the stomach, which mainly is maintained even postprandially, and the presence of gastrointestinal enzymes, will serve to denude ingested particles of their surface-adsorbed molecules but then re-adsorption of novel entities will occur in the less acidic small bowel lumen.
There are many exogenous inorganic particles are man-made particles comprising titanium dioxide or silicates/aluminosilicates. Titanium dioxide (designated E171 in Europe) is used for whitening and brightening foods, especially for confectionary, white sauces and dressings, and certain powdered foods.
Titanium dioxide (designated E171 in Europe) is used for whitening and brightening foods, especially for confectionary, white sauces and dressings, and certain powdered foods. It is also used in the pharmaceutical industry as an opacity agent. Titanium dioxide is typically found in gut tissue in the anatase polymorphic form and is a 100-200 nm diameter spherical particle that is resistant to gastrointestinal degradation. Particulate silicates and aluminosilicates (E554, E556 and E559 in Europe) are used in the food industry as anti-caking agents and to allow the flow of powders, and some are present in cheeses, sugars and powdered milks. In the UK, the major five food sources of particulate silicates are salt, drinking powders, chewing gum, instant pot savory snacks and icing sugar.Overall, intake of dietary inorganic microparticles in the UK has been estimated to be about 40 mg/person/day (35 mg for the silicates and 5 mg for titanium dioxide) which equates to a staggering daily exposure of 101214 particles/person.
How are the partciles taken up in the gut? M-cell-uptake (transcytosis) at the surface of intestinal lymphoid aggregates is the quintessential pathway for gut particle uptake and is very well described, especially for large nanoparticles (20-100 nm) and small microparticles (100-500 nm). Hydrophobic particles appear to be much better taken up than hydrophilic particles, and generally, small particles are better taken up than large ones with, perhaps, an optimal size of around 50 nm diameter.
Other sources of nanoparticles (NM) relevant for oral exposure comprise mainly cosmetics (sunscreen, lipsticks, skin creams, toothpaste) and food (packaging, storage life sensors, food additives, juice clarifiers). Whereas NMs in food are intended to be ingested, nanoparticles for instance in cosmetics and ingredients in food packaging may accidently get into the gastrointestinal tract. Major materials used in these products are: silver, and metal oxides of zinc, silica, and titanium. Nanosilver (Ag) is used in food packaging. According to the Woodrow Wilson Nanotechnology Consumer Products Inventory 2011, Ag nanoparticles are the most commonly used new NM in consumer products followed by TiO2, ZnO, platinum (Pt) and silicium oxide NMs (http://www.nanotechproject.org/inventories/consumer/). Although gold NMs are also used in cosmetics, food packaging, beverage and toothpaste their main applications are in the medical field.
Decrease of particle size in the nanoscale has been identified as a main parameter for the increased toxicity of different materials. Polystyrene, for instance, is a very biocompatible polymer used in cell culture. Nanoparticles, however, made from this material are cytotoxic.
Compared to other metal and metal oxide nanoparticles intake of TiO2 by food is relatively high at 5 mg TiO2/person/d .Metal and metal oxide nanoparticles can accumulate in plants and in animals of the food chain. That is worrisome.
A number of factors effect uptake of particles by the gut. Even in healthy individuals gastrointestinal transit is by far not constant and shows considerable variation through the large intestine . These effects are known to influence oral bioavailability of conventional drugs but are even more important for the effects of NMs because NMs readily adsorb proteins. Mucus represents an efficient acellular barrier. Mucus consists of mucin proteins (highly glycosylated extracellular proteins with characteristic gel-forming properties), antiseptic proteins (lysozyme) and other proteins (lactoferrin), inorganic salts and water. The major functions are the protection and the lubrication of the underlying tissue. The saliva, which is produced by the salivary glands, mainly consists of water (up to 99.5%), inorganic salts, proteins, and mucins. The high molecular weight mucin MG1 can bind to the surface of the epithelium and build the so-called mucus layer, displaying the acellular barrier of the oral cavity The mucus of the following parts, stomach and small and large intestine, is mainly produced by intraepithelial cells, and hickness increases from proximal to distal parts of the small and large intestine . Depending on the method used for the determination, the thickness of the mucus layer shows marked variation..The characteristics facilitating the passage through human mucus are relatively well known: electrostatic repulsion from negatively charged sugar moieties favors the penetration of positively charged hydrophilic molecules; the passage of lipophilic compounds is slow. Viruses, like the Norwalk virus with a size of 38 nm and human papilloma virus with a size of 55 nm diffused in human mucus as rapidly as they do in water These findings suggest that the surface charge plays a crucial role in the transport rates of nanoparticles through a mucus layer
In addition to particle size, dose and duration of the exposure are important for the interpretation of the data. In addition to particle size, dose and duration of the exposure are important. There is a size-dependent decrease of the uptake from 34% for 50 nm particles to 26% for 100 nm particles , and dose and duration of the exposure are also important for absorption and uptake of NM.
Changes in mucus composition induced by Ag nanoparticles (Jeong et al., 2010), polystyrene particles and diesel exhaust increased mucus permeability and permeation of small molecules by a factor of 5. Thus NM enter more quickly through disease barriers.
The adherence of polystyrene nanoparticles to inflamed colonic mucosa was much higher than to normal mucosa. Inflammation appears to increase uptake and permeation of NMs in vitro and in vivo. Inflammation caused by Yersinia pseudotuberculosis increases the uptake of 100 nm carboxyl polystyrene particles in cell monolayers and in intestinal biopsies. Other factors of absorption include pH and thickness of the mucus layer, the gastrointestinal flora and in gastrointestinal passage time (motility)
Whereas plasma membranes restrict the cellular access for metal ions like silver cations, silver nanoparticles were readily internalized and intracellular silver concentrations were much higher than for silver ions. Studies for uptake and toxicity should, therefore, include AgNO3 for silver nanoparticles (Trojan horse effect) or bulk material.. Absorption may also be altered by a changed metabolization by enterocytes. Polystyrene and silver particles have been shown to inhibit the activity of cytochrome P450 enzymes, of note
To avoid foods rich in titanium oxide nanoparticles you should avoid processed foods, and especially candy. This information may make one question if these NM have any impact on the surge of colitis seen ion the general poplulation? How about autoimmune diseases? How about general inflammation, for if NM damage the intestinal barrier, inflammation results and it’s attendant consequences.
“MIND” is an acronym for Mediterranean-DASH Diet Intervention for Neurodegenerative Delay. Both the Mediterranean and DASH diets have been found to reduce the risk for hypertension, myocardial infarction, and stroke.
The MIND diet has 15 dietary components, including 10 “brain-healthy” food groups and five unhealthy groups (ie, red meat, butter and stick margarine, cheese, pastries and sweets, and fried or fast food). To stick to the MIND diet, a person has to limit intake of the designated unhealthy foods, especially butter (<1 tablespoon/day), sweets and pastries, whole fat cheese, and fried or fast food (<1 serving a week for any of the three). As for the brain-healthy foods, a person would need to eat at least three servings of whole grains, a green leafy vegetable, and one other vegetable each day, along with having a glass of wine. They would also need to snack most days on nuts, have beans every other day or so, and eat poultry and berries at least two times a week (berries are the only fruits allowed in the MIND diet) and fish at least once a week. The overall rate of change in cognitive score was a decline of 0.8 standardized score units per year. In mixed models adjusted for a variety of relevant factors, including age, sex, education, total energy intake, APOE4 carrier status, and participation in cognitive activities, the MIND diet score was “positively and statistically significantly” associated with slower decline in global cognitive score (β = 0.0092; P < .0001) and with five cognitive domains, especially episodic memory, semantic memory, and perceptual speed, the researchers report. If a person is eating in a manner that is heart healthy, that’s probably also going to be brain healthy, because the brain does use so much of the nutrients and the oxygen that are carried in the vascular system, and as you age, if your brain isn’t getting enough nutrients and oxygen, it is going to be less likely to be able to deal with other factors that cause Alzheimer’s disease or other dementias.
Dietary intakes of berries and flavonoids in relation to cognitive declineResults: Greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline (eg, for a global score averaging all 6 cognitive tests, for blueberries: p-trend ¼ 0.014 and mean difference ¼ 0.04, 95% confidence interval [CI] ¼ 0.01–0.07, comparing extreme categories of intake; for strawberries: p-trend ¼ 0.022 and mean difference ¼ 0.03, 95% CI ¼ 0.00–0.06, comparing extreme categories of intake), after adjusting for multiple potential confounders. These effect estimates were equivalent to those we found for approximately 1.5 to 2.5 years of age in our cohort, indicating that berry intake appears to delay cognitive aging by up to 2.5 years. Additionally, in further supporting evidence, greater intakes of anthocyanidins and total flavonoids were associated with slower rates of cognitive decline (p-trends ¼ 0.015 and 0.053, respectively, for the global score). Interpretation: Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults.
When it comes to single or multiple nutrients, the evidence has also exploded. For example, omega-3 fatty acids or E vitamins, curcumin, vitamin D, and caffeinated foods: These are all different dietary components that may or may not play a role in development of Alzheimer disease. Dr Martha Clare Morris and her colleagues from Rush University presented a great paper that studied very specific brain-healthy eating patterns, which she calls the MIND diet, with the results suggesting a reduction in the likelihood of developing cognitive impairment significantly over several years. omega-3 fatty acids: First of all, not all omega-3’s are created equal. DHA and EPA have the most evidence for reducing a person’s risk of developing cognitive decline. The key here is that certain people with different genes may respond preferentially; people with an ApoE4 gene may respond favorably while people without that gene may respond less. When it comes to Alzheimer’s treatment, those omega-3’s didn’t pan out in terms of randomized studies, but omega-3’s used for Alzheimer’s prevention or risk reduction are something we want to think about. Also, when it comes to personalized medicine based on genes, we can focus on Alzheimer disease in a new area called clinical precision medicine, where we look not only at genetics, but also at people’s individual biologies, nutritional patterns, and lifestyle patterns, and then give a clinically precise approach for treatment or prevention. For example, if a person has high homocysteine levels, then B complex vitamins—folic acid, B12, and B6—in randomized studies have been shown to slow overall brain atrophy as well as increase memory function. The key take-home point here is that B complex therapy only works in patients who have high homocysteine levels and those who have an adequate level of omega-3’s in the blood. When it comes to blueberries, you’ve heard about flavonols. Dark cocoa powder may be effective for boosting memory. You can’t just eat one blueberry and think you’re going to prevent or cure Alzheimer disease—it doesn’t work that way. But in the Nurses’ Health Study, a half a cup of blueberries two to three times a week was shown to delay the onset of cognitive decline.
Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects the Cocoa, Cognition, and Aging (CoCoA) Study : This dietary intervention study provides evidence that regular CF consumption can reduce some measures of age-related cognitive dysfunction, possibly through an improvement in insulin sensitivity. These data suggest that the habitual intake of flavanols can support healthy cognitive function with age. Abstract—Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing 990 mg (high flavanols), 520 mg (intermediate flavanols), or 45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P0.05) lower in subjects assigned to high flavanols (38.1010.94 and 104.1028.73 seconds, respectively) and intermediate flavanols (40.2011.35 and 115.9728.35 seconds, respectively) in comparison with those assigned to low flavanols (52.6017.97 and 139.2343.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.506.75 versus 22.308.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained 40% of composite z score variability through the study period (partial r2 0.4013; P0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.
Results Significant increases in regional perfusion across the brain were observed following consumption of the high flavanol drink relative to the low flavanol drink, particularly in the anterior cingulate cortex and the central opercular cortex of the parietal lobe.
Transgenic growth hormone mice (TGM) are a recognized model of accelerated aging with characteristics including chronic oxidative stress, reduced longevity, mitochondrial dysfunction, insulin resistance, muscle wasting, and elevated inflammatory processes. Growth hormone/IGF-1 activate the Target of Rapamycin known to promote aging. TGM particularly express severe cognitive decline. We previously reported that a multi-ingredient dietary supplement (MDS) designed to offset five mechanisms associated with aging extended longevity, ameliorated cognitive deterioration and significantly reduced age-related physical deterioration in both normal mice and TGM. Here we report that TGM lose more than 50% of cells in midbrain regions, including the cerebellum and olfactory bulb. This is comparable to severe Alzheimer’s disease and likely explains their striking agerelated cognitive impairment. We also demonstrate that the MDS completely abrogates this severe brain cell loss, reverses cognitive decline and augments sensory and motor function in aged mice. Additionally, histological examination of retinal structure revealed markers consistent with higher numbers of photoreceptor cells in aging and supplemented mice. We know of no other treatment with such efficacy, highlighting the potential for prevention or amelioration of human neuropathologies that are similarly associated with oxidative stress, inflammation and cellular dysfunction. Environ. Mol. Mutagen. 57:382–404, 2016.
A dietary supplement containing ingredients commonly found in health food stores appears to prevent the decline in brain structure and function typically seen in Alzheimer’s disease, the results of an animal study indicate. Dietary Supplement May Prevent Cognitive Decline In a mouse model of accelerated aging and severe cognitive decline, a combination of vitamins and minerals, as well as nutraceuticals, such as beta carotene, bioflavonoids, cod liver oil, flax seed, garlic, and green tea extract, not only maintained brain cell numbers and mass and cognitive function but also appeared to prevent deterioration of sight and smell. Mechanisms of degenration , which include oxidative stress, inflammation, and mitochondrial dysfunction, “happen in a multitude of species as they get older” and are not “something that is specifically a human phenomenon that has been attempted to be recreated in a mouse model.
Effects of treatment with a multi-ingredient dietary supplement designed to ameliorate key mechanisms of aging showed treatment was associated with reduced anxiety-like behaviors, augmented discrimination of environmental context, improved motor balance, and improved visual and olfactory acuity. This was correlated with positive morphological changes and higher neuronal populations in the cerebellum and olfactory bulb, increased overall brain cell numbers and improved brain function. Intact olfaction is strongly indicative of suppression of neuronal degeneration. Retinal atrophy (associated with AMD) was also diminished in supplemented mice. Given that MDS treatment has been shown to signifi-cantly reduce oxidative damage, boost mitochondrial function [Lemon et al 2008a,b; Aksenov et al., 2010; Aksenov et al., 2013] and alleviate symptoms of inflammation [Lemon et al., 2005], suggests that neuronal protection and sensory function are likely attributed to diminishing oxidative/inflammatory stress and improved energy balance. The extent of functional benefits attained by our MDS here and in earlier studies [Lemon et al., 2003, 2005, 2008a,b; Aksenov et al., 2010, 2013; Long et al., 2012; Hutton et al., 2015’ strongly suggests that aging animals retain the capacity to support youthful phenotypes and that powerful impacts can be achieved through multi-ingredient dietary supplementation that addresses the multifactorial nature of aging organisms.
Vitamin brands are as follows: a ¼ Cell Life; b ¼ Jamieson vitamins; c ¼ Jarrow Formulas; d ¼ Lifebrand; e ¼ Natural Factors; f ¼ Naka; g ¼ Promatrix; h ¼ Swiss vitamins; i ¼ Vitamin Power Inc
That is typically because our cells are working in such a complex way that we have many mechanisms that are occurring simultaneously, and when something’s going wrong, it’s usually knocking everything out of balance. When the level of one particular component is increased in the cells, “you tend to also knock everything out of whack.
Previous research by the team showed that the supplement extended longevity and reduced cognitive and age-related physical deterioration in both normal mice and transgenic growth hormone mice (TGM). TGM are characterized by accelerated aging accompanied by severe cognitive decline, as well long-term oxidative stress, insulin resistance, and other traits. For the current study, the team mated heterozygous TGM and normal mice to create equal numbers of TGM and normal mice with a similar genetic background. The mice were then randomly assigned at weaning either to receive a liquid form of the supplement every day, with the doses of the ingredients adjusted to correspond to the amounts recommended for humans, or to be left untreated.
The mice then underwent a series of somatosensory tests to determine the severity of age-related losses in motor coordination and overall mobility. Their brains were examined for histologic changes, and the degree of apoptosis and changes in cell counts were assessed. Single-photon emission computed tomography and positron-emission tomography scanning was also performed.
The team found that compared with normal mice, untreated TGM displayed brain cell losses, deterioration of sensory function, and reductions in cerebral metabolic rate and blood perfusion that were equivalent to those seen in patients with Alzheimer’s disease.
Specifically, the mice had greater than a 50% loss at a cellular level, a 36% reduction in brain mass, and at least twofold reductions in brain metabolism and blood flow at 12 months. Furthermore, in the untreated TGM, motor and cognitive functions were severely compromised.
Although the supplement did not have significant effects on brain cell numbers, brain weight, or brain metabolism or perfusion in normal mice, it had striking effects in TGM.
With the supplement, brain mass and brain cell density were maintained at levels seen in young mice. Brain metabolic activity was comparable to that in control mice, with no significant difference between the groups. Moreover, the supplement was associated with a twofold increase in brain perfusion in TGM.
The results also showed that the supplement restored cognitive function in TGM and led to significant improvements in motor coordination. It also appeared to reduce anxiety, allowing TGM to explore “unsafe/novel” environments.
The team found that the supplement appeared to offset deterioration of visual acuity in TGM. It was associated with increases in the thickness of the retinal outer nuclear layer and outer segment of 26% and 29%, respectively, in TGM compared with untreated mice.
TGM that received the supplement also showed improvements in olfactory sensitivity and greater numbers of mitral cells in the olfactory bulb in comparison with untreated mice. Inasmuch as olfactory loss is associated with an increased risk of developing severe neurodegenerative conditions, the researchers say these findings suggest that the supplement may be offsetting neurodegeneration throughout the brain.
total brain volume losses were lower in individuals with higher baseline vitamin B12 levels, whereas the opposite was true of those with increased homocysteine levels. Vitamin B12 and tHcy [total homocysteine] might be independent predictors of markers of brain aging in elderly individuals without dementia. Venous blood samples were collected at baseline, from which circulating levels of vitamin B12, red blood cell folate, and sulfur amino acids were determined. These were correlated with changes in brain tissue volumes and total white matter hyperintensity (WMH) over 6 years
Between baseline and the 6-year follow-up, the mean total brain tissue (TBT) volume decreased from 74.3% to 71.6% of the total cranial volume (P < .001), whereas the mean WMH volume increased from 0.0004% to 0.0007% (P < .001).
Multiadjusted linear mixed model analysis revealed that increased baseline levels of vitamin B12 and holotranscobalamin (the biologically active fraction of B12) were associated with a decreased rate of TBT volume loss, at respective beta values of 0.048 (P < .001) and 0.040 (P = .002) for each standard deviation increase. Furthermore, the researchers found that each standard deviation increase in total homocysteine levels was linked to more rapid rates of TBT volume loss, at a beta value of -0.035 (P = .02). Increases in total homocysteine levels were also associated with increases in the progression of WMH in individuals with a systolic blood pressure >140 mmHg, at 0.000019 per standard deviation increase (P = .047).
Results In the multi-adjusted linear mixed models, among 501 participants (300 women [59.9%]; mean [SD] age, 70.9 [9.1] years), higher baseline vitamin B12 and holotranscobalamin levels were associated with a decreased rate of total brain volume loss during the study period: for each increase of 1 SD, β (SE) was 0.048 (0.013) for vitamin B12 (P < .001) and 0.040 (0.013) for holotranscobalamin (P = .002). Increased total homocysteine levels were associated with faster rates of total brain volume loss in the whole sample (β [SE] per 1-SD increase, –0.035 [0.015]; P = .02) and with the progression of white matter hyperintensity among participants with systolic blood pressure greater than 140 mm Hg (β [SE] per 1-SD increase, 0.000019 [0.00001]; P = .047). No longitudinal associations were found for red blood cell folate and other sulfur amino acids.
Conclusions and Relevance This study suggests that both vitamin B12 and total homocysteine concentrations may be related to accelerated aging of the brain. Randomized clinical trials are needed to determine the importance of vitamin B12 supplementation on slowing brain aging in older adults.
Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B6 and B12 in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and vitamin B6 (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans.
A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63–0.90] in the active treatment group and 1.08% [0.94–1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category.
Conclusions and Significance
The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer’s disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer’s disease, trials are needed to see if the same treatment will delay the development of Alzheimer’s disease.
the single-center, randomized VITACOG study, in which 271 individuals older than 70 years who had mild cognitive impairment received supplementation with high-dose folic acid and vitamins B6 and B12. They lost less brain compared to people who had normal homocysteine and normal vitamin levels, meaning that those with high levels of homocysteine or with clinical or biochemical vitamin deficiency can benefit from supplementation.
Presented here at the Alzheimer’s Association International Conference (AAIC) 2012, results from an open-label extension (OLE) trial of a medical nutrition product (Souvenaid, Nutricia/Danone) showed that memory performance continued to improve in drug-naïve patients with mild AD for up to 48 weeks.
Efficacy of Souvenaid in Mild Alzheimer’s Disease: Results from a Randomized, Controlled Trial Abstract: Souvenaid aims to improve synapse formation and function. An earlier study in patients with Alzheimer’s disease (AD) showed that Souvenaid increased memory performance after 12 weeks in drug-naïve patients with mild AD. The Souvenir II study was a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial to confirm and extend previous findings in drug-naïve patients with mild AD. Patients were randomized 1:1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. The primary outcome was the memory function domain Z-score of the Neuropsychological Test Battery (NTB) over 24 weeks. Electroencephalography (EEG) measures served as secondary outcomes as marker for synaptic connectivity. Assessments were done at baseline, 12, and 24 weeks. The NTB memory domain Z-score was significantly increased in the active versus the control group over the 24-week intervention period (p=0.023; Cohen’s d=0.21; 95% confidence interval [-0.06]–[0.49]). A trend for an effect was observed on the NTB total composite z- score (p=0·053). EEG measures of functional connectivity in the delta band were significantly different between study groups during 24 weeks in favor of the active group. Compliance was very high (96.6% [control] and 97.1% [active]). No difference between study groups in the occurrence of (serious) adverse events. This study demonstrates that Souvenaid is well tolerated and improves memory performance in drug-naïve patients with mild AD. EEG outcomes suggest that Souvenaid has an effect on brain functional connectivity, supporting the underlying hypothesis of changed synaptic activity.
To investigate the effect of a medical food on cognitive function in people with mild Alzheimer’s disease (AD).
A total of 225 drug-naïve AD patients participated in this randomized, double-blind controlled trial. Patients were randomized to active product, Souvenaid, or a control drink, taken once-daily for 12 weeks. Primary outcome measures were the delayed verbal recall task of the Wechsler Memory Scale–revised, and the 13-item modified Alzheimer’s Disease Assessment Scale–cognitive subscale at week 12.
At 12 weeks, significant improvement in the delayed verbal recall task was noted in the active group compared with control (P = .021). Modified Alzheimer’s Disease Assessment Scale–cognitive subscale and other outcome scores (e.g., Clinician Interview Based Impression of Change plus Caregiver Input, 12-item Neuropsychiatric Inventory, Alzheimer’s disease Co-operative Study–Activities of Daily Living, Quality of Life in Alzheimer’s Disease) were unchanged. The control group neither deteriorated nor improved. Compliance was excellent (95%) and the product was well tolerated.
Supplementation with a medical food including phosphatide precursors and cofactors for 12 weeks improved memory (delayed verbal recall) in mild AD patients. This proof-of-concept study justifies further clinical trials.
Synapse loss, he said, is an early event in the AD process. By providing the nutritional precursors and cofactors for synapse formation, researchers hope to support the formation and function of synapses.
The once-a-day drink contains a patented nutrient combination with the following ingredients:
Eicospentaenoic acid, 300 mg
Docosahexaenoic acid, 1200 mg
Phospholipids 106 mg
Choline, 400 mg
Uridine monophosphate, 625 mg
Vitamin E (alpha-tocopherol equivalents), 40 mg
Selenium, 60 µg
Vitamin B12, 3 µg
Vitamin B6, 1 mg
Folic acid, 400 µg
The current findings also showed there was a statistically significant beneficial effect on memory in favor of Souvenaid at 6 months. Of the 238 patients who completed this trial, 198 participants entered the OLE study. Of these participants, 181 completed it. The results revealed that at 48 weeks, the product was well tolerated with no serious adverse events. In addition, the compliance rate was more than 90% The OLE results also revealed that memory performance as measured by the neuropsychological test battery (NTB) continued to improve significantly in study participants who received Souvenaid for the full 48 weeks (P = .025). In addition, in the group that received placebo for the first 24 weeks, there was a significant improvement in NTB memory scores during the OLE following conversion to the active treatment (P = .009).
Makary and Daniel noted that a “medical error” may or may not cause harm to the patient and defined an error as:
An unintended act (either of commission or omission);
An act that does not achieve its intended outcome;
The failure of a planned action to be completed (an error of execution);
The use of a wrong plan to achieve an aim (an error of planning); or
Deviation from the process of care.
Cognitive-proximity biases; the Kübler-Ross sequence of denial and anger; the psychological need to assign blame; the risks associated with procedural management of cancer or cardiovascular disease in an unstable, aging population; and retrospective cause-and-effect attributions are all driving factors in random catastrophic lethal events being attributed inappropriately to healthcare provider-caused errors.
Preventable systematic lethal or egregious human errors do occur, but overall they are relatively small in number compared with random, unpreventable events. Oversight efforts to prevent these errors (eg, electronic health records) can have the opposite unintended consequence of increased random events, because quality provider-patient clinical ‘face time’ is reduced.
Other clinicians from the “error happens” camp believe that systems, not humans, are largely to blame for errors. A registered nurse explained. “System errors, not people intent on making mistakes, are the main culprit. Tort reform is much needed because many family members who feel the pain of loss are eager to punish someone for a loved one’s death.”
Errors are not the fault of physicians but of systems. Human disease and top causes of death have changed from acute infections to chronic problems, but the mindset that drugs and interventions that worked so well in the past are also the solution in today’s world is wrong. It is a sign that medicine needs to change with the times. We should be putting more emphasis on preventive medicine, holistic approaches, and physiological nutrition, because the drugs and interventions are doing nothing to stop the top killers.
There may no doubt that many deaths are due to clinician, nursing, and pharmacy error. Yet nowhere is it accounted for that the population as a whole is horribly sick from their own devices
Death certificates depend on International Classification of Diseases (ICD) codes for cause of death, so causes such as human and system errors are not recorded on them.
People tend to hold overly favorable views of their abilities in many social and intellectual domains. The authors suggest that this overestimation occurs, in part, because people who are unskilled in these domains suffer a dual burden: Not only do these people reach erroneous conclusions and make unfortunate choices, but their incompetence robs them of the metacognitive ability to realize it. Across 4 studies, the authors found that participants scoring in the bottom quartile on tests of humor, grammar, and logic grossly overestimated their test performance and ability. Although their test scores put them in the 12th percentile, they estimated themselves to be in the 62nd. Several analyses linked this miscalibration to deficits in metacognitive skill, or the capacity to distinguish accuracy from error. Paradoxically, improving the skills of the participants, and thus increasing their metacognitive competence, helped them recognize the limitations of their abilities.
Has it ever seemed to you that less competent people rate their competence higher than it actually is, while more competent people humbly rate theirs lower?
It’s not just your imagination. This is a genuine cognitive bias called the Dunning-Kruger Effect.
The Dunning-Kruger experiments behind the research focused on cognitive tasks (logic, grammar, and evaluating humor), but similar disparities exist in other areas. In self-assessment of IQ, below-average people overestimated their score and those above average underestimated.
Studies of healthy and unhealthy behaviors are handicapped when they rely on self-reporting because test subjects tend to improve their evaluation. In self-evaluations of driving ability, job performance, and even immunity to bias, we tend to polish our image.
This is called the Lake Wobegone Effect, named after the town where “all the children are above average.”
Notice that there are two different categories of error:
(1) the error where there is a preferred answer and most people are biased toward giving that answer (“How much snack food do you eat?” or “How popular would you say you are?” or “How good a driver are you?”), and
(2) the error where bias changes depending on actual competence, with the less and more competent groups rating themselves too high and too low, respectively.
Let’s look at the second category, where the two extremes make opposite errors. The Dunning-Kruger research hypothesizes that the competent overestimate others’ skill levels. But the error is more complicated for the incompetent—they overestimate their own skill level and they lack the metacognition to realize their error. In other words, they were too incompetent to recognize their own incompetence. Improving their metacognitive skills drove down their self-assessment scores as they became better evaluators of their own limitations.
According to the CDC, in 2013, 611,105 people died of heart disease, 584,881 died of cancer, and 149,205 died of chronic respiratory disease—the top three causes of death in the U.S. The newly calculated figure for medical errors puts this cause of death behind cancer but ahead of respiratory disease. Analyzing medical death rate data over an eight-year period, Johns Hopkins patient safety experts have calculated that more than 250,000 deaths per year are due to medical error in the U.S. Their figure, published May 3 in The BMJ, surpasses the U.S. Centers for Disease Control and Prevention’s third leading cause of death—respiratory disease, which kills close to 150,000 people per year. Most errors represent systemic problems, including poorly coordinated care, fragmented insurance networks, the absence or underuse of safety nets, and other protocols, in addition to unwarranted variation in physician practice patterns that lack accountability.
The authors also suggest that hospitals carry out a rapid and efficient independent investigation into deaths to determine whether error played a role. A root cause analysis approach would help while offering the protection of anonymity. It’s public pressure that brings about change. Hospitals have no incentive to publicize errors; neither do doctors or any other provider. However, such a major step as adding error information to death certificates is unlikely if not accompanied by tort reform. Medical Error Is Third Leading Cause of Death in US
Analyzing medical death rate data over an eight-year period, Johns Hopkins patient safety experts have calculated that more than 250,000 deaths per year are due to medical error in the U.S. Their figure, published May 3 in The BMJ, surpasses the U.S. Centers for Disease Control and Prevention’s third leading cause of death—respiratory disease, which kills close to 150,000 people per year.
The Johns Hopkins team says the CDC’s way of collecting national health statistics fails to classify medical errors separately on the death certificate. The researchers are advocating for updated criteria for classifying deaths on death certificates.
“Incidence rates for deaths directly attributable to medical care gone awry haven’t been recognized in any standardized method for collecting national statistics,” says Martin Makary, professor of surgery at the Johns Hopkins University School of Medicine and an authority on health reform. “The medical coding system was designed to maximize billing for physician services, not to collect national health statistics, as it is currently being used.”
In 1949, Makary says, the U.S. adopted an international form that used International Classification of Diseases billing codes to tally causes of death.
“At that time, it was under-recognized that diagnostic errors, medical mistakes, and the absence of safety nets could result in someone’s death,” says Makary, “and because of that, medical errors were unintentionally excluded from national health statistics.”
In their study, the researchers examined four separate studies that analyzed medical death rate data from 2000 to 2008. Then, using hospital admission rates from 2013, they extrapolated that based on a total of 35,416,020 hospitalizations, 251,454 deaths stemmed from a medical error, which the researchers say now translates to 9.5 percent of all deaths each year in the U.S.
According to the CDC, in 2013, 611,105 people died of heart disease, 584,881 died of cancer, and 149,205 died of chronic respiratory disease—the top three causes of death in the U.S. The newly calculated figure for medical errors puts this cause of death behind cancer but ahead of respiratory disease.
“Top-ranked causes of death as reported by the CDC inform our country’s research funding and public health priorities,” Makary says. “Right now, cancer and heart disease get a ton of attention, but since medical errors don’t appear on the list, the problem doesn’t get the funding and attention it deserves.”
The researchers caution that most medical errors aren’t due to inherently bad doctors, and that reporting these errors shouldn’t be addressed by punishment or legal action. Rather, they say, most errors represent systemic problems, including poorly coordinated care, fragmented insurance networks, the absence or underuse of safety nets, and other protocols, in addition to unwarranted variation in physician practice patterns that lack accountability.
“Unwarranted variation is endemic in health care,” Makary says. “Developing consensus protocols that streamline the delivery of medicine and reduce variability can improve quality and lower costs in health care. More research on preventing medical errors from occurring is needed to address the problem.”
Whole grain intake is related to a clear dose-dependent reduction in the risk for coronary heart disease, stroke, cardiovascular disease, total cancer deaths, and all-cause mortality, the authors of a new meta-analysis report. They observed a similar relationship between whole grains and the risk for respiratory disease, diabetes, infectious disease, and deaths not related to cardiovascular disease or cancer.
Conclusions This meta-analysis provides further evidence that whole grain intake is associated with a reduced risk of coronary heart disease, cardiovascular disease, and total cancer, and mortality from all causes, respiratory diseases, infectious diseases, diabetes, and all non-cardiovascular, non-cancer causes. These findings support dietary guidelines that recommend increased intake of whole grain to reduce the risk of chronic diseases and premature mortality.
Results 45 studies (64 publications) were included. The summary relative risks per 90 g/day increase in whole grain intake (90 g is equivalent to three servings—for example, two slices of bread and one bowl of cereal or one and a half pieces of pita bread made from whole grains) was 0.81 (95% confidence interval 0.75 to 0.87; I2=9%, n=7 studies) for coronary heart disease, 0.88 (0.75 to 1.03; I2=56%, n=6) for stroke, and 0.78 (0.73 to 0.85; I2=40%, n=10) for cardiovascular disease, with similar results when studies were stratified by whether the outcome was incidence or mortality. The relative risks for morality were 0.85 (0.80 to 0.91; I2=37%, n=6) for total cancer, 0.83 (0.77 to 0.90; I2=83%, n=11) for all causes, 0.78 (0.70 to 0.87; I2=0%, n=4) for respiratory disease, 0.49 (0.23 to 1.05; I2=85%, n=4) for diabetes, 0.74 (0.56 to 0.96; I2=0%, n=3) for infectious diseases, 1.15 (0.66 to 2.02; I2=79%, n=2) for diseases of the nervous system disease, and 0.78 (0.75 to 0.82; I2=0%, n=5) for all non-cardiovascular, non-cancer causes. Reductions in risk were observed up to an intake of 210-225 g/day (seven to seven and a half servings per day) for most of the outcomes.Intakes of specific types of whole grains including whole grain bread, whole grain breakfast cereals, and added bran, as well as total bread and total breakfast cereals were also associated with reduced risks of cardiovascular disease and/or all cause mortality, but there was little evidence of an association with refined grains, white rice, total rice, or total grains.
The authors defined one serving of all grains or whole or refined grains as 30 g, equivalent to one slice of bread or one serving of breakfast cereal. The researchers defined a serving of pasta as 150 g, and a serving of white or brown rice as 167.25 g. They studied changes in the risk for illness or mortality per 90-g increase in whole grain intake and between the lowest and highest intakes, up to 210 to 225 g (7 – 7.5 servings) per day. The summary relative risk for coronary heart disease for high vs low whole grain consumption was 0.79 (Pheterogeneity = 0.63; n = 7 studies), equivalent to a risk reduction of 21%. For stroke, the pooled relative risk for high vs low intake was 0.87 (Pheterogeneity = .21; n = 6 studies), a risk reduction of 13%. High vs low whole grain intake also was associated with a 16% reduction in the risk for cardiovascular disease (summary relative risk, 0.84; Pheterogeneity = .48; n = 10 studies). In a similar comparison for total cancer, the summary relative risk was 0.89 (Pheterogeneity = .003; n = 6 studies), and for all-cause mortality, the pooled relative risk was 0.82 (Pheterogeneity < 0.001; n = 11 studies), translating into risk reductions of 11% and 18%, respectively.
In the dose–response analyses, the summary relative risk for coronary heart disease per 90 g/day was 0.81 (n = 7 studies), or a 19% reduction in risk. The summary relative risk for stroke per 90 g/day was 0.88 (n = 6), equivalent to a 12% risk reduction. For cardiovascular disease, the summary relative risk was 0.78 (n = 10) or a 22% risk reduction per 90 g/day. Total cancer was associated with a summary relative risk per 90 g/day of 0.85 (Pheterogeneity = .16), a 15% reduction in risk. The summary relative risk for all-cause mortality per 90 g/day was 0.83 (Pheterogeneity < .001), a reduction of 17%.
The authors also observed reductions of 19%, 36%, 20%, and 21%, respectively, in the relative risk for mortality from respiratory disease, diabetes, infectious disease, and all deaths not related to cancer or cardiovascular disease between high and low intakes of whole grains. Most of the studies showed “a clear dose-response relation with further reductions with intakes up to seven to seven and a half servings a day (210-225 g/day),” the authors write. These findings suggest that “even moderate increases in whole grain intake could reduce the risk of premature mortality.”
Take great care not to promote whole grain foods with high sugar and salt content.
There have been anecdotal reports of the efficacy of dietary
therapy, especially starvation, for the treatment of epilepsy
since Biblical times. Clinical and
research interest in the ketogenic diet was renewed in the
early 1990s after a 2-year-old boy with intractable seizures
was treated with the ketogenic diet at the Johns Hopkins
Hospital. The diet is now well established in the
medical community and is even reimbursed by insurance
companies, including Blue Cross and Blue Shield. The main indication for the ketogenic diet is the presence of seizures that are difficult to control, such as those that occur in Lennox-Gastaut syndrome. However, the efficacy of the diet appears to be independent of seizure type.
Maydell BV, Wyllie E, Akhtar N, et al. Efficacy of the ketogenic diet
in focal versus generalized seizures. Pediatr Neurol. 2001;25:208 –212. Abstract:
Most reports of the ketogenic diet have focused on its efficacy for generalized seizures. Few data are available regarding its effect on focal seizures. We retrospectively studied patients (mean = 7.5 years of age) with medically intractable epilepsy treated by the ketogenic diet. The predominant seizure types in each patient were classified as generalized (100 patients) or focal (34 patients) based on ictal electroencephalograms (EEGs) or seizure semiology and interictal EEG. A seizure reduction of more than 50% compared with baseline was seen in nine patients (27%) with focal seizures and 46 patients (46%) with generalized seizures at 3 months, in 10 patients (30%) with focal seizures and 46 patients (46%) with generalized seizures at 6 months, and in eight patients (24%) with focal seizures and 42 patients (42%) with generalized seizures at 12 months. Differences were not significant. Outcome tended to be better in patients younger than 12 years of age compared with the older age group, but the difference was significant at 6 months only. Our results suggest that some patients with intractable focal epilepsy may respond favorably to the ketogenic diet and that this option should be considered if epilepsy surgery is not possible.
Because the ketogenic diet is associated with major
shifts in cerebral energy metabolism, some authors caution
against using the diet in patients with certain metabolic
disorders. These include pyruvate carboxylase deficiency,
mitochondrial disorders, and fatty acid oxidation problems.
The actual dietary components are individually calculated
for each patient, incorporating both daily calories,
fluids, and the ratio of fat to protein and carbohydrates,
ranging from 2:1 to 4:1, with higher ratios more restrictive. Young children and infants as well as adolescents are typically started on a 3:1 ratio to be able to provide extra protein and to allow adolescents
increased choices of foods. Most other children are
started on a 4:1 ratio. This is treatment for epilepsy. carbohydrates are typically 5 to 10 g/day, with the remainder of calories as fat. Although fluids and calories are traditionally restricted to improve ketosis, there is little evidence regarding the necessity of this. Older children are given computergenerated
menus that offer 3 daily meals and a snack. Fluids are usually also restricted to 80% of daily needs. There are
some data to suggest that the initial period of fasting is not
necessary for long-term ketosis and that the diet can be
initiated at home without hospitalization. Is a Fast Necessary When Initiating the ketogenic diet Acute problems periodically seen during fasting include hypoglycemia, vomiting, dehydration, and food refusal.
The patient’s medications are also reviewed and adjusted
during the admission to make sure that they are free of
carbohydrates as many, especially liquids, have high carbohydrate
content that can interfere with ketosis.
Another version of the ketogenic diet, based on
medium-chain triglyceride (MCT) oil, was developed in the
late 1960s.22 The motivation for development of this diet was
that MCT oils are more strongly ketogenic than longer fatty
acids. This reduces the amount of fat that is required in the
diet, allowing a larger amount of protein and even carbohydrates.
This version of diet, however, can cause gastrointestinal
distress in patients (stomach cramps and diarrhea) and is
used now only occasionally. MCT oil is often incorporated in
the classic ketogenic diet for a variety of reasons, including
increasing the protein and carbohydrate allowances, countering
constipation, or improving dyslipidemia. The medium chain triglyceride diet and intractable epilepsy.
Maintenance of the diet is difficult and common culprits of sugar are new medications or food additives that are labeled as “sugar free” but may still contain large amounts of carbohydrates such as maltodextrin, sorbitol, starch, or fructose. If ketones are not 4 or more than 160 mg/dL, then a 24-hour fast with clear liquids can be used to improve ketosis rapidly.
Acidosis is a major concern during both diet initiation and
acute intercurrent illnesses. It is important that the patient and
family understand signs of acidosis and how to hydrate with
carbohydrate-free fluids. Most children on the diet have a low
baseline acidosis, with HCO3 – of 12 to 18 mg/dL. The issue of whether carnitine supplementation should be used (or acylcarnitine levels checked) is still controversial. COmmon symptoms on the diet are:
Nausea/vomiting during initiation
Constipation (classic diet)
Diarrhea (MCT version)
The incidence of renal calculi in children on the ketogenic
diet is 5 to 6%.27,28 The diet can cause hypercalciuria,
urine acidification, and hypocitraturia, increasing the risk of
uric acid and, less commonly, calcium phosphate and oxalate
stones. Increased hydration and oral polycitrates (Polycitra K™, 2 mEq/kg/day divided twice daily) if there is a family or personal history of kidney stones.
Another known side effect is hyperlipidemia.29–31 A
prospective study of children on the classic diet showed
significant elevations of total cholesterol, triglycerides, and
the atherogenic apolipoprotein B containing lipoproteins
(LDL and VLDL). There was a significant reduction of the
antiatherogenic apolipoprotein A-containing lipoproteins
• Reduced carbohydrates for 24 hours • Fasting starts the evening before admission
Day 1 (Monday) • Admitted to the hospital • Fasting continues • Fluids restricted to 60–75 mL/kg • Blood glucose monitored every 6 hours • Use carbohydrate-free medications • Parents begin educational program
Day 2 (Tuesday) • Dinner, given as “eggnog,” providing 1/3 of calculated maintenance dinner calorie allowance • Blood glucose checks discontinued after dinner • Parents begin to check urine ketones periodically • Education continues
Day 3 (Wednesday) • Breakfast and lunch given as eggnog, providing 1/3 of maintenance breakfast and lunch calorie allowance • Dinner (still eggnog), increased to 2/3 of maintenance dinner calorie allowance • Education continues ·
Day 4 (Thursday) • Breakfast and lunch given as 2/3 of maintenance meal allowance • Dinner is first full ketogenic meal (not eggnog) • Education completed
Day 5 (Friday) • Full ketogenic diet breakfast (calories) given • Prescriptions reviewed and follow-up arranged • Child discharged to home
Modified Atkins Diet Protocol (22) • Copy of a carbohydrate counting guide provided to the family • Carbohydrates described in detail and restricted to 10 grams per day for the first month • Fats (e.g., 36% heavy whipping cream, oils, butter, mayonnaise) encouraged • Clear, carbohydrate-free, fluids and calories not restricted • Low-carbohydrate multivitamin (Unicap M™) and calcium (Calcimix™) supplementation prescribed • Urine ketones checked semiweekly and weight weekly • Medications unchanged for at least the first month, but changed if necessary to tablet or sprinkle (non liquid) preparations • Low-carbohydrate, store-bought products (e.g., shakes, candy bars, baking mixes) discouraged for at least the first month • Complete blood count, complete metabolic profile (SMA-20), fasting lipid profile, urine calcium, and urine creatinine obtained at baseline, 3, and 6 months
Abstract: Concentrations of acetyl–coenzyme A and nicotinamide adenine dinucleotide (NAD+) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body d-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.
Per the article: Cellular metabolites such as acetyl–coenzyme A (acetyl-CoA) and nicotinamide adenine dinucleotide (NAD+ ) influence gene expression by serving as cofactors for epigenetic modifiers that mediate posttranslational modification of histones . The activity of histone acetyltransferases (HATs) is dependent on nuclear acetyl-CoA concentrations and the deacetylase activity of class III HDACs, also called sirtuins, is dependent on NAD+ concentrations (4). Class I (HDAC1, 2, 3, 8), class II (HDAC4, 5, 6, 7, 9, 10), and class IV (HDAC11) HDACs are zincdependent enzymes, but endogenous regulators are not known. Small-molecule inhibitors of class I and class II HDACs include butyrate, a product of bacterial anaerobic fermentation (5). Butyrate is closely related to b-hydroxybutyrate (bOHB) (Fig. 1A), the major source of energy for mammals during prolonged exercise or starvation (6). Accumulation of bOHB in blood increases to 1 to 2 mM during fasting when the liver switches to fatty acid oxidation (7, 8), and to even higher concentrations during prolonged fasting (6 to 8 mM) – To determine whether bOHB might have HDAC inhibitor activity was the goal in the article.Our observation that bOHB is an endogenous HDAC inhibitor present in organisms at millimolar concentrations during prolonged fasting and CR reveals an example of integration between metabolic status and epigenetic changes. We show that changes in histone acetylation and gene expression caused by bOHB promote stress resistance in the kidney.For example, low-carbohydrate diets that induce substantial ketogenesis are broadly neuroprotective and enhance resistance of neurons to oxidative damage Ketone bodies are protective against oxidative stress in neocortical neurons. In addition, reduction in HDAC activity by either genetic manipulation or chemical inhibition extends life span in Drosophila Longevity Regulation by Drosophila Rpd3 Deacetylase and Caloric Restriction and Life extension in Drosophila by feeding a drug Inhibition of HDACs by bOHB might contribute to the beneficial effect of ketogenic diets and may be one mechanism by which calorie restriction confers health benefits. Finding Ponce de Leon’s Pill Challenges in Screening for Anti-Aging Molecules and Interventions to Slow Aging in Humans Are We Ready and Caloric restriction and its mimetics.
Abstract: The role of very-low-carbohydrate ketogenic diets (VLCKD) in the long-term management of obesity is not well established. The present meta-analysis aimed to investigate whether individuals assigned to a VLCKD (i.e. a diet with no more than 50 g carbohydrates/d) achieve better long-term body weight and cardiovascular risk factor management when compared with individuals assigned to a conventional lowfat diet (LFD; i.e. a restricted-energy diet with less than 30 % of energy from fat). Through August 2012, MEDLINE, CENTRAL, ScienceDirect, Scopus, LILACS, SciELO, ClinicalTrials.gov and grey literature databases were searched, using no date or language restrictions, for randomised controlled trials that assigned adults to a VLCKD or a LFD, with 12 months or more of follow-up. The primary outcome was body weight. The secondary outcomes were TAG, HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), systolic and diastolic blood pressure, glucose, insulin, HbA1c and C-reactive protein levels. A total of thirteen studies met the inclusion/exclusion criteria. In the overall analysis, five outcomes revealed significant results. Individuals assigned to a VLCKD showed decreased body weight (weighted mean difference 20·91 (95 % CI 21·65, 20·17) kg, 1415 patients), TAG (weighted mean difference 20·18 (95 % CI 20·27, 20·08) mmol/l, 1258 patients) and diastolic blood pressure (weighted mean difference 21·43 (95 % CI 22·49, 20·37) mmHg, 1298 patients) while increased HDL-C (weighted mean difference 0·09 (95 % CI 0·06, 0·12) mmol/l, 1257 patients) and LDL-C (weighted mean difference 0·12 (95 % CI 0·04, 0·2) mmol/l, 1255 patients). Individuals assigned to a VLCKD achieve a greater weight loss than those assigned to a LFD in the long term; hence, a VLCKD may be an alternative tool against obesity.
Abstract: Patients with idiopathic Parkinson disease (PD) may suffer from impairment of complex I activity involving—but not limited to—dopaminergic neurons of the substantia nigra pars compacta (SNpc).1 The resulting mitochondrial dysfunction could help explain some of the clinical manifestations of the illness. A recent study of isolated mouse brain mitochondria exposed to the complex I inhibitor, 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), found that mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly increased when D--hydroxybutyrate (DHB) was added to the preparation, apparently by a complex II-dependent mechanism.2 These findings in mice suggested that dietinduced elevation of blood ketones (DHB and acetoacetate [AcAc]) to concentrations sufficient to replace a substantial proportion of glucose as the brain’s fuel might bring about symptomatic improvement in patients with PD by bypassing the presumed complex I defect and boosting mitochondrial function and ATP production. In addition, in vitro and in vivo evidence that DHB protects against MPTP-induced neurotoxicity2,3 suggests that sufficiently prolonged nutritional hyperketonemia might also help delay the progression of idiopathic PD. To increase blood ketones to concentrations within the “therapeutic” range (2 to 7 mmol/L), patients are usually maintained on a “4:1 hyperketogenic diet” (HKD), consisting (by weight) of 4 parts fat and 1 part of a carbohydrate-protein mixture).4 Although this kind of diet has been used successfully for decades for treatment of children and adults with medication-resistant seizure disorders,5 it is difficult to follow; moreover, after prolonged use, significant elevations may occur in serum low-density lipoprotein (LDL) cholesterol and other potentially atherogenic serum lipids.6 Given evidence that ketones crossing the bloodbrain barrier may bypass or compensate for the defect in complex I activity implicated in PD, it seemed desirable to test whether a HKD can benefit patients with PD. However, before attempting an extensive outpatient study, we deemed it essential to determine in a small series whether: 1) ambulatory patients with PD would be able to prepare a HKD in their own homes and remain on it for at least 4 weeks; 2) substitution of mono- and polyunsaturated fats for saturated fats, wherever possible, would mitigate the increases in the serum total cholesterol concentration expected from a very high fat diet; 3) evidence could be obtained to support the clinical safety of the HKD approach in the patients with PD. At best, the improved scores support the safety of the HKD approach. A placebo effect on UPDRS scores has been documented in numerous pharmacologic trials in PD10 and could have occurred in our patients. The studies of isolated mouse brain mitochondria exposed to MPTP, referred to earlier,2 found that ketone supplementation increases the generation of reactive oxygen species, thought by many to be a key mediator of nigral neuron degeneration. This observation is a cause for concern; however, the same investigation also showed DHB to be neuroprotective in the presence of MPTP. Moreover, despite extensive experience with HKDs for treatment of drugresistant epilepsy, there have been no reports of neurodegeneration attributable to diet-induced hyperketonemia sustained for many years. Ketone Bodies, Potential Therapeutic Uses – d-β-Hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease –
A ketogenic diet has been shown to reduce the generation of reactive oxygen species through its effect on uncoupling proteins. It also increases levels of antioxidant agents including catalase and glutathione through its inhibitory action on histone deacetylases and activation of the Nrf2 pathway. 9.1. The Ketogenic Diet Increases Mitochondrial Uncoupling Protein Levels. The process of oxidative phosphorylation generates reactive oxygen species. The extent of reactive oxygen species generation correlates strongly with the potential difference across the inner mitochondrial membrane. Uncoupling proteins (UCPs) can reduce this potential difference by allowing the entry of protons into the mitochondrial matrix. Although this “mild” uncoupling may incur a small reduction in ATP generated through oxidative phosphorylation, its overall net effect is to enhance respiration and ATP levels through a reduction in reactive oxygen species formation and protection from apoptotic events . A ketogenic diet appears to promote UCP activity, specifically the activity of UCP2, UCP4, and UCP5 with a corresponding decline in reactive oxygen species . 9.2. Ketones Inhibit Histone Deacetylases. The ketone betahydroxybutyrate has a direct, dose-dependent inhibitory activity on class I histone deacetylases (HDACs) including HDAC1, HDAC3, and HDAC4. The ketone acetoacetate has also been shown to inhibit class I and class IIa HDACs. Beta-hydroxybutyrate’s inhibition of HDAC promotes the acetylation of histone H3 lysine 9 and histone H3 lysine 14 and increases the transcription of genes regulated by FOXO3A. These include genes leading to the expression of the antioxidant enzymes mitochondrial superoxide dismutase and catalase . 9.3. A Ketogenic Diet Leads to the Activation of the Nrf2 Pathway. The ketogenic diet raises glutathione levels in the hippocampus of rats . This is thought to occur through the Nrf2 (nuclear factor erythroid 2-related factor) pathway. When the ketogenic diet is first initiated, there is a temporary increase in oxidative stress.This may be activating Nrf2, since, a week after the temporary rise in oxidative stress, there is increased expression of Nrf2. Three weeks after the start of the diet, oxidative stress declines to below baseline levels and Nrf2 remains raised. the diet, oxidative stress declines to below baseline levels and Nrf2 remains raised . 10. The Effect of the Ketogenic Diet on ATP Levels A ketogenic diet enhances ATP production. The administration of beta-hydroxybutyrate immediately following bilateral common carotid artery ligation in a mouse model of global cerebral ischaemia preserves ATP levels . Feeding mice a ketogenic diet for three weeks resulted in increased levels of ATP and the ATP/ADP ratio in the brain . The improvement in ATP levels may partly be explained through the ability of the ketogenic diet to reduce oxidative stress. Although the diet may reduce reactive oxygen species generation through an increase in UCP activity, any reduction in oxidative phosphorylation incurred through UCP activity is outweighed by the enhancement of respiration and associated ATP production occurring as a result of reduced oxidative stress. A ketogenic diet also appears to preserve ATP levels in the event of mitochondrial respiratory chain dysfunction, possibly through the replenishment of TCA cycle intermediates . Beta-hydroxybutyrate attenuates the decrease in ATP production caused by a defect in complex I of the electron transport chain. It is thought to increase levels of the TCA intermediate succinate, which bypasses complex I when entering the TCA cycle [65, 72]. This carries considerable implications for MS, since defects in complex I within the electron transport chain have been observed in white matter lesions as well as in “normal” regions of the motor cortex [39, 73]. Ketones can also preserve ATP levels if complex II of the electron transport chain is inhibited, but this effect shows some regional specificity . 11. The Effect of the Ketogenic Diet on Mitochondrial Biogenesis Mitochondrial biogenesis within the rat hippocampus and cerebellar vermis is increased by the ketogenic diet [75, 76]. Although the precise pathway for this is not known, it is thought to involve the PGC1? family of transcriptional coactivators, which promote transcription factors including NRF-1, NRF-2, and ERR? . 12. The Effect of the Ketogenic Diet on Inflammation The anti-inflammatory effect of a ketogenic diet has been demonstrated in a murine model of lipopolysaccharideinduced fever . In a rat model of MS, the diet suppressed the expression of inflammatory cytokines and enhanced CA1 hippocampal synaptic plasticity and long-term potentiation, which resulted in improved learning, memory, and motor ability . The anti-inflammatory effect of a ketogenic diet may partly be explained through the inhibition of the NLRP3 inflammasome by beta-hydroxybutyrate in a manner that is independent of starvation-induced mechanisms such as AMPK, autophagy, or glycolytic inhibition. The NLRP3 inflammasome is responsible for the cleavage of procaspase-1 into caspase-1 and the activation of the cytokines IL-1? and IL-18. Its inhibition prevents IL-1? and IL-18 generation and their downstream effects . 13. The Neuroprotective Properties of the Ketogenic Diet Ketone bodies play a neuroprotective role in animal models of neurodegeneration [69, 81]. ATP-sensitive potassium channels (K ATP channels) located on the cell surface of neurons stabilize neuronal excitability. Ketones promote an “open state” of these channels and confer neuronal stability . K ATP channels also play a role in mitochondrial function and in cell death. The “open state” of K ATP channels located on the inner mitochondrial membrane prevents the formation of mitochondrial permeability transition pores (MPTPs) that can lead to mitochondrial swelling and cell death. Acetoacetate and beta-hydroxybutyrate have been shown to increase the threshold for calcium-induced MPTP formation . 14. The Regional Variation of the Effect of Ketones in the Mouse Cerebellum Despite these seemingly positive effects on mitochondrial bioenergetics, the effects of a ketogenic diet on mitochondria within the mouse brain are not homogenous and some results appear conflicting. Although the study on the murine model of EAE demonstrated improved CA1 synaptic plasticity, in another study, on rats, although a KD prevented age-related morphological changes within the outer layer of the dentate gyrus of the cerebellum, it produced negative changes within the CA1 region . In a study on rats fed a ketogenic diet for 8 weeks, antioxidant status was elevated within the hippocampus but not in the cerebral cortex and antioxidant activity was seen to be reduced within the cerebellum.Despite its high fat component, the ketogenic diet is safe and even beneficial for cardiometabolic risk factors . It has been in continuous use for almost a century for the treatment of epilepsy and has shown good tolerability, even in children . Current ketogenic diet protocols involve a range of options, which encourages patient compliance. Where compliance may pose a challenge, mimicry of various components of the ketogenic pathway through the use of ketone analogues may offer a palatable therapeutic option . Supplementation with ketones to induce ketosis has also shown an acceptable safety and tolerability profile .
Statins positively impact plasma low-density lipoprotein cholesterol, inflammation and vascular endothelial function (VEF). Carbohydrate restricted diets (CRD) improve atherogenic dyslipidemia, and similar to statins, have been shown to favorably affect markers of inflammation and VEF. No studies have examined whether a CRD provides additional benefit beyond that achieved by habitual statin use. We hypothesized that a CRD (<50 g carbohydrate/d) for 6 weeks would improve lipid profiles and insulin sensitivity, reduce blood pressure, decrease cellular adhesion and inflammatory biomarkers, and augment VEF (flow-mediated dilation and forearm blood flow) in statin users. Participants (n = 21; 59.3 ± 9.3 y, 29.5 ± 3.0 kg/m2 ) decreased total caloric intake by approximately 415 kcal at 6 weeks (P < .001). Daily nutrient intakes at baseline (46/36/17% carb/fat/pro) and averaged across the intervention (11/58/28% carb/fat/pro) demonstrated dietary compliance, with carbohydrate intake at baseline nearly 5-fold greater than during the intervention (P < .001). Compared to baseline, both systolic and diastolic blood pressure decreased after 3 and 6 weeks (P < .01). Peak forearm blood flow, but not flow-mediated dilation, increased at week 6 compared to baseline and week 3 (P ≤ .03). Serum triglyceride, insulin, soluble E-Selectin and intracellular adhesion molecule-1 decreased (P < .01) from baseline at week 3, and this effect was maintained at week 6. In conclusion, these findings demonstrate that individuals undergoing statin therapy experience additional improvements in metabolic and vascular health from a 6 weeks CRD as evidenced by increased insulin sensitivity and resistance vessel endothelial function, and decreased blood pressure, triglycerides, and adhesion molecules.
Of interest re: SCFA : Cocobiota Implications for Human Health. << Current advances in molecular microbiology and analytical food chemistry suggest that processed cocoa beans and cocoa-based products may contain some substances and chemical compounds of microbial and fungal origin which are highly beneficial to human health. Taking into consideration the obvious significance of bacterial and fungal species in the process of fermentation of cocoa beans as well as their potential impact on human health, we introduce herein a new term COCOBIOTA. We define cocobiota as a specific unity of bacteria and fungi which drives spontaneous postharvest fermentation of cocoa beans and which may have some health effect through various primary and secondary metabolites of bacterial-fungal origin present in cocoa powder and dark chocolate
Reversal of Diabetic Nephropathy by a Ketogenic Diet <<< Intensive insulin therapy and protein restriction delay the development of nephropathy in a variety of conditions, but few interventions are known to reverse nephropathy. Having recently observed that the ketone 3-beta-hydroxybutyric acid (3-OHB) reduces molecular responses to glucose, we hypothesized that a ketogenic diet, which produces prolonged elevation of 3-OHB, may reverse pathological processes caused by diabetes. To address this hypothesis, we assessed if prolonged maintenance on a ketogenic diet would reverse nephropathy produced by diabetes. In mouse models for both Type 1 (Akita) and Type 2 (db/db) diabetes, diabetic nephropathy (as indicated by albuminuria) was allowed to develop, then half the mice were switched to a ketogenic diet. After 8 weeks on the diet, mice were sacrificed to assess gene expression and histology. Diabetic nephropathy, as indicated by albumin/creatinine ratios as well as expression of stress-induced genes, was completely reversed by 2 months maintenance on a ketogenic diet. However, histological evidence of nephropathy was only partly reversed. These studies demonstrate that diabetic nephropathy can be reversed by a relatively simple dietary intervention. Whether reduced glucose metabolism mediates the protective effects of the ketogenic diet remains to be determined.
The Effect of a Low-Carbohydrate, Ketogenic Diet on Nonalcoholic Fatty Liver Disease A Pilot Study << Abstract Nonalcoholic fatty liver disease is an increasingly common condition that may progress to hepatic cirrhosis. This pilot study evaluated the effects of a low-carbohydrate, ketogenic diet on obesity-associated fatty liver disease. Five patients with a mean body mass index of 36.4 kg/m2 and biopsy evidence of fatty liver disease were instructed to follow the diet (<20 g/d of carbohydrate) with nutritional supplementation for 6 months. Patients returned for group meetings biweekly for 3 months, then monthly for the second 3 months. The mean weight change was − 12.8 kg (range 0 to − 25.9 kg). Four of 5 posttreatment liver biopsies showed histologic improvements in steatosis (P = .02) inflammatory grade (P = .02), and fibrosis (P = .07). Six months of a lowcarbohydrate, ketogenic diet led to significant weight loss and histologic improvement of fatty liver disease. Further research is into this approach is warranted.
Also: Middle and Long-Term Impact of a Very Low-Carbohydrate Ketogenic Diet on Cardiometabolic Factors A Multi-Center, Cross-Sectional, Clinical Study.Results All the predetermined goals—namely safety, reduction of body weight and CV risk factors levels—have been reached with a significant reduction of body weight (from baseline to 4 weeks (-7 ± 5 kg, p\0.001), from 4 to 12 weeks (-5 ± 3 kg, p\0.001), no changes from 12 weeks to 12 months; waistline (from baseline to 4 weeks (-7 ± 4 cm, p\0.001), from 4 to 12 weeks (-5 ± 7 cm, p\0.001), no changes from 12 weeks to 12 months; fatty mass (from baseline to 4 weeks (-3.8 ± 3.8 %, p\0.001), from 4 to 12 weeks (-3.4 ± 3.5 %, p\0.001), no changes from 12 weeks to 12 months; SBP from baseline to 3 months (-10.5 ± 6.4 mmHg, p\0.001), no further changes after 1 year of observation). Conclusion the tested VLCD diet suggested by trained general physicians in the setting of clinical practice seems to be able to significantly improve on the middle-term a number of anthropometric, haemodynamic and laboratory with an overall good tolerability.
Beyond weight loss- a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. <<< Very-low-carbohydrate diets or ketogenic diets have been in use since the 1920s as a therapy for epilepsy and can, in some cases, completely remove the need for medication. From the 1960s onwards they have become widely known as one of the most common methods for obesity treatment. Recent work over the last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors. The possibility that modifying food intake can be useful for reducing or eliminating pharmaceutical methods of treatment, which are often lifelong with significant side effects, calls for serious investigation. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possible mechanisms for the therapeutic actions of the ketogenic diet on different diseases. The present review also questions whether there are still some preconceived ideas about ketogenic diets, which may be presenting unnecessary barriers to their use as therapeutic tools in the physician’s hand.
Ketosis, ketogenic diet and food intake control a complex relationship lThough the hunger-reduction phenomenon reported during ketogenic diets is well-known, the underlying molecular and cellular mechanisms remain uncertain. Ketosis has been demonstrated to exert an anorexigenic effect via cholecystokinin (CCK) release while reducing orexigenic signals e.g., via ghrelin. However, ketone bodies (KB) seem to be able to increase food intake through AMP-activated protein kinase (AMPK) phosphorylation, gamma-aminobutyric acid (GABA) and the release and production of adiponectin. The aim of this review is to provide a summary of our current knowledge of the effects of ketogenic diet (KD) on food control in an effort to unify the apparently contradictory data into a coherent picture.
Ketogenic Diet in Neuromuscular and Neurodegenerative DiseasesAn increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson’s disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review.
High-Fat and Ketogenic Diets in Amyotrophic Lateral Sclerosis << In summary, there are strong epidemiologic data showing that malnutrition is a common symptom of amyotrophic lateral sclerosis both in humans and in mice and may contribute to disease progression. There is also epidemiologic evidence that increased dietary fat and cholesterol intake might reduce the risk of amyotrophic lateral sclerosis and the rate disease progression. Finally, data from animal studies strongly suggest that increasing dietary intake of fat ameliorates disease progression. However, determining whether amyotrophic lateral sclerosis patients should be treated with a high-fat or ketogenic diet can be based only on randomized double-blind placebo-controlled interventional trials.
Limited Effect of Dietary Saturated Fat on Plasma Saturated Fat in the Context of a Low Carbohydrate Diet A hypocaloric carbohydrate restricted diet (CRD) had two striking effects: (1) a reduction in plasma saturated fatty acids (SFA) despite higher intake than a low fat diet, and (2) a decrease in inflammation despite a significant increase in arachidonic acid (ARA).These findings are consistent with the concept that dietary saturated fat is efficiently metabolized in the presence of low carbohydrate, and that a CRD results in better preservation of plasma ARA.
A Low-Carbohydrate, Whole-Foods Approach to Managing Diabetes and PrediabetesWe recently proposed that the biological markers improved by carbohydrate restriction were precisely those that define the metabolic syndrome (MetS), and that the common thread was regulation of insulin as a control element. We specifically tested the idea with a 12-week study comparing two hypocaloric diets (approximately 1,500 kcal): a carbohydrate-restricted diet (CRD) (%carbohydrate:fat:protein = 12:59:28) and a low-fat diet (LFD) (56:24:20) in 40 subjects with atherogenic dyslipidemia. Both interventions led to improvements in several metabolic markers, but subjects following the CRD had consistently reduced glucose (-12%) and insulin (-50%) concentrations, insulin sensitivity (-55%), weight loss (-10%), decreased adiposity (-14%), and more favorable triacylglycerol (TAG) (-51%), HDL-C (13%) and total cholesterol/HDL-C ratio (-14%) responses. In addition to these markers for MetS, the CRD subjects showed more favorable responses to alternative indicators of cardiovascular risk: postprandial lipemia (-47%), the Apo B/Apo A-1 ratio (-16%), and LDL particle distribution. Despite a threefold higher intake of dietary saturated fat during the CRD, saturated fatty acids in TAG and cholesteryl ester were significantly decreased, as was palmitoleic acid (16:1n-7), an endogenous marker of lipogenesis, compared to subjects consuming the LFD. Serum retinol binding protein 4 has been linked to insulin-resistant states, and only the CRD decreased this marker (-20%). The findings provide support for unifying the disparate markers of MetS and for the proposed intimate connection with dietary carbohydrate. The results support the use of dietary carbohydrate restriction as an effective approach to improve features of MetS and cardiovascular risk.
Abstract: Abnormal distribution of plasma fatty acids and increased inflammation are prominent features of metabolic syndrome. We tested whether these components of metabolic syndrome, like dyslipidemia and glycemia, are responsive to carbohydrate restriction. Overweight men and women with atherogenic dyslipidemia consumed ad libitum diets very low in carbohydrate (VLCKD) (1504 kcal:%CHO:fat:protein = 12:59:28) or low in fat (LFD) (1478 kcal:%CHO:fat:protein = 56:24:20) for 12 weeks. In comparison to the LFD, the VLCKD resulted in an increased proportion of serum total n-6 PUFA, mainly attributed to a marked increase in arachidonate (20:4n-6), while its biosynthetic metabolic intermediates were decreased. The n-6/n-3 and arachidonic/eicosapentaenoic acid ratio also increased sharply. Total saturated fatty acids and 16:1n-7 were consistently decreased following the VLCKD. Both diets significantly decreased the concentration of several serum inflammatory markers, but there was an overall greater anti-inflammatory effect associated with the VLCKD, as evidenced by greater decreases in TNF-alpha, IL-6, IL-8, MCP-1, E-selectin, I-CAM, and PAI-1. Increased 20:4n-6 and the ratios of 20:4n-6/20:5n-3 and n-6/n-3 are commonly viewed as pro-inflammatory, but unexpectedly were consistently inversely associated with responses in inflammatory proteins. In summary, a very low carbohydrate diet resulted in profound alterations in fatty acid composition and reduced inflammation compared to a low fat diet.
The above shows that despite being higher in saturated fat, a ketogenic diet decreases circulating levels of saturated fatty acids
Beneficial effects of ketogenic diet in obese diabetic subjects. < Excellent study showing sustained weight loss over a year period – also blood lipids improvement were sustained as well using a well-crafted ketogenic diet. Diet guidelines included meat, fish, poultry, full fat cheeses, green vegetables, 5 T/day olive oil, flax seed oil.
Excess carbohydrates taken in above which you can metabolize will be converted to fat. This results in increased circulating levels of saturated fats, especially palimitoleic acid (16:1) and exacerbates insulin resistance.
If you have insulin resistance – restricting sugars and starches can profoundly benefit all risk factors. Insulin resistance is a carbohydrate intolerant state.
Higher levels of palmitoleic acid in the blood stream or adipose tissue are associated with bad outcomes such as: obesity, hypertriglyceridemia, hyperglycemia, inflammation, metabolic syndrome, heart failure, increased incidence of prostate cancer, coronary artery disease, diabetes, etc
Even without high blood sugar, increase pamitoleic acid in the blood is associated with increased risk of developing type 2 diabetes.
Effects of Step-Wise Increases in Dietary Carbohydrate on Circulating Saturated Fatty Acids and Palmitoleic Acid in Adults with Metabolic SyndromeRecent meta-analyses have found no association between heart disease and dietary saturated fat; however, higher proportions of plasma saturated fatty acids (SFA) predict greater risk for developing type-2 diabetes and heart disease. These observations suggest a disconnect between dietary saturated fat and plasma SFA, but few controlled feeding studies have specifically examined how varying saturated fat intake across a broad range affects circulating SFA levels. Sixteen adults with metabolic syndrome (age 44.9¡9.9 yr, BMI 37.9¡6.3 kg/m2 ) were fed six 3-wk diets that progressively increased carbohydrate (from 47 to 346 g/day) with concomitant decreases in total and saturated fat. Despite a distinct increase in saturated fat intake from baseline to the low-carbohydrate diet (46 to 84 g/day), and then a gradual decrease in saturated fat to 32 g/day at the highest carbohydrate phase, there were no significant changes in the proportion of total SFA in any plasma lipid fractions. Whereas plasma saturated fat remained relatively stable, the proportion of palmitoleic acid in plasma triglyceride and cholesteryl ester was significantly and uniformly reduced as carbohydrate intake decreased, and then gradually increased as dietary carbohydrate was re-introduced. The results show that dietary and plasma saturated fat are not related, and that increasing dietary carbohydrate across a range of intakes promotes incremental increases in plasma palmitoleic acid, a biomarker consistently associated with adverse health outcomes.
Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humansBackground: Cross-sectional studies have identified a high intake of simple sugars as an important dietary factor predicting nonalcoholic fatty liver disease (NAFLD). Objective: We examined whether overfeeding overweight subjects with simple sugars increases liver fat and de novo lipogenesis (DNL) and whether this is reversible by weight loss. Design: Sixteen subjects [BMI (kg/m2 ): 30.6 6 1.2] were placed on a hypercaloric diet (.1000 kcal simple carbohydrates/d) for 3 wk and, thereafter, on a hypocaloric diet for 6 mo. The subjects were genotyped for rs739409 in the PNPLA3 gene. Before and after overfeeding and after hypocaloric diet, metabolic variables and liver fat (measured by proton magnetic resonance spectroscopy) were measured. The ratio of palmitate (16:0) to linoleate (18:2n26) in serum and VLDL triglycerides was used as an index of DNL. Results: Carbohydrate overfeeding increased weight (6SEM) by 2% (1.8 6 0.3 kg; P , 0.0001) and liver fat by 27% from 9.2 6 1.9% to 11.7 6 1.9% (P = 0.005). DNL increased in proportion to the increase in liver fat and serum triglycerides in subjects with PNPLA3-148II but not PNPLA3-148MM. During the hypocaloric diet, the subjects lost 4% of their weight (3.2 6 0.6 kg; P , 0.0001) and 25% of their liver fat content (from 11.7 6 1.9% to 8.8 6 1.8%; P , 0.05). Conclusions: Carbohydrate overfeeding for 3 wk induced a .10-fold greater relative change in liver fat (27%) than in body weight (2%). The increase in liver fat was proportional to that in DNL. Weight loss restores liver fat to normal. These data indicate that the human fatty liver avidly accumulates fat during carbohydrate overfeeding and support a role for DNL in the pathogenesis of NAFLD
Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation.Abnormal distribution of plasma fatty acids and increased inflammation are prominent features of metabolic syndrome. We tested whether these components of metabolic syndrome, like dyslipidemia and glycemia, are responsive to carbohydrate restriction. Overweight men and women with atherogenic dyslipidemia consumed ad libitum diets very low in carbohydrate (VLCKD) (1504 kcal:%CHO:fat:protein = 12:59:28) or low in fat (LFD) (1478 kcal:%CHO:fat:protein = 56:24:20) for 12 weeks. In comparison to the LFD, the VLCKD resulted in an increased proportion of serum total n-6 PUFA, mainly attributed to a marked increase in arachidonate (20:4n-6), while its biosynthetic metabolic intermediates were decreased. The n-6/n-3 and arachidonic/eicosapentaenoic acid ratio also increased sharply. Total saturated fatty acids and 16:1n-7 were consistently decreased following the VLCKD. Both diets significantly decreased the concentration of several serum inflammatory markers, but there was an overall greater anti-inflammatory effect associated with the VLCKD, as evidenced by greater decreases in TNF-alpha, IL-6, IL-8, MCP-1, E-selectin, I-CAM, and PAI-1. Increased 20:4n-6 and the ratios of 20:4n-6/20:5n-3 and n-6/n-3 are commonly viewed as pro-inflammatory, but unexpectedly were consistently inversely associated with responses in inflammatory proteins. In summary, a very low carbohydrate diet resulted in profound alterations in fatty acid composition and reduced inflammation compared to a low fat diet.
Serum saturated fatty acids containing triacylglycerols are better markers of insulin resistance than total serum triacylglycerol concentrations.results: We identified 45 different TGs in serum. Serum TGs containing saturated and monounsaturated fatty acids were positively, while TGs containing essential linoleic acid (18:2 n-6) were negatively correlated with HOMA-IR. Specific serum TGs that correlated positively with HOMA-IR were also significantly positively related to HOMA-IR when measured in very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs) and LDL, but not in HDL subfraction 2 (HDL(2)) or 3 (HDL(3)). Analyses of proportions of esterified fatty acids within lipoproteins revealed that palmitic acid (16:0) was positively related to HOMA-IR when measured in VLDL, IDL and LDL, but not in HDL(2) or HDL(3). Monounsaturated palmitoleic (16:1 n-7) and oleic (18:1 n-9) acids were positively related to HOMA-IR when measured in HDL(2) and HDL(3), but not in VLDL, IDL or LDL. Linoleic acid was negatively related to HOMA-IR in all lipoproteins Conclusions: Serum concentrations of specific TGs, such as TG(16:0/16:0/18:1) or TG(16:0/18:1/18:0), may be more precise markers of insulin resistance than total serum TG concentrations.
During a follow-up of five to seven years 33 out of 1222 middle-aged men initially free of coronary heart disease sustained fatal or non-fatal myocardial infarction or died suddenly. The fatty-acid composition of serum triglycerides, phospholipids, and cholesterol esters had been measured at the start of the surveillance in these men and in a control group of 64 men matched for age, serum cholesterol and triglyceride concentrations, blood pressure, obesity, smoking, and one-hour glucose tolerance. Palmitic and stearic acids of phospholipids were significantly higher and linoleic and most polyunsaturated fatty acids, including arachidonic acid and eicosapentaenoic acid, of phospholipids were lower in the subjects who sustained coronary events compared with the controls. Linoleic acid tended to correlate negatively with blood pressure while other polyunsaturated fatty acids, especially eicosapentaenoic acid, exhibited a negative correlation with blood pressure and relative body weight in the controls but not in the subjects who sustained coronary events. These findings suggest that the fatty-acid pattern of serum phospholipids is an independent risk factor for coronary heart disease.
For saturated fat, three to 12 prospective cohort studies for each association were pooled (five to 17 comparisons with 90,501-339,090 participants). Saturated fat intake was not associated with all cause mortality (relative risk 0.99, 95% confidence interval 0.91 to 1.09), CVD mortality (0.97, 0.84 to 1.12), total CHD (1.06, 0.95 to 1.17), ischemic stroke (1.02, 0.90 to 1.15), or type 2 diabetes (0.95, 0.88 to 1.03). There was no convincing lack of association between saturated fat and CHD mortality (1.15, 0.97 to 1.36; P=0.10). For trans fats, one to six prospective cohort studies for each association were pooled (two to seven comparisons with 12,942-230,135 participants). Total trans fat intake was associated with all cause mortality (1.34, 1.16 to 1.56), CHD mortality (1.28, 1.09 to 1.50), and total CHD (1.21, 1.10 to 1.33) but not ischemic stroke (1.07, 0.88 to 1.28) or type 2 diabetes (1.10, 0.95 to 1.27). Industrial, but not ruminant, trans fats were associated with CHD mortality (1.18 (1.04 to 1.33) v 1.01 (0.71 to 1.43)) and CHD (1.42 (1.05 to 1.92) v 0.93 (0.73 to 1.18)). Ruminant trans-palmitoleic acid was inversely associated with type 2 diabetes (0.58, 0.46 to 0.74). The certainty of associations between saturated fat and all outcomes was “very low.” The certainty of associations of trans fat with CHD outcomes was “moderate” and “very low” to “low” for other associations.
Saturated fats are not associated with all cause mortality, CVD, CHD, ischemic stroke, or type 2 diabetes, but the evidence is heterogeneous with methodological limitations. Trans fats are associated with all cause mortality, total CHD, and CHD mortality, probably because of higher levels of intake of industrial trans fats than ruminant trans fats. Dietary guidelines must carefully consider the health effects of recommendations for alternative macronutrients to replace trans fats and saturated fats.
Serum fatty acids and the risk of coronary heart disease – [Men who had heart attacks had higher serum palmitic acid (16:0) and a 68% greater risk of heart disease] To examine the relation between serum fatty acids and coronary heart disease (CHD), the authors conducted a nested case-control study of 94 men with incident CHD and 94 men without incident CHD who were enrolled in the Usual Care group of the Multiple Risk Factor Intervention Trial between December 1973 and February 1976. After confirming the stability of the stored serum samples, the authors measured serum fatty acid levels by gas-liquid chromatography and examined their association with CHD. In all multivariate models, levels of the cholesterol ester saturated fatty acid palmitic acid (16:0) were directly associated with CHD risk (standardized odds ratio = 1.68; 95% confidence interval 1.10-2.55 in the model that adjusted for total plasma cholesterol level). Levels of the phospholipid omega-3 fatty acid docosapentaenoic acid (22:5) were inversely associated with CHD risk in the two multivariate models that controlled for the effects of total plasma cholesterol level or high density lipoprotein cholesterol to total plasma cholesterol ratio (standardized odds ratio = 0.58; 95% confidence interval 0.38-0.89 in the first model that controlled for total plasma cholesterol level). In contrast to the first two multivariate models, levels of the docosahexaenoic acid (22:6) were inversely associated with CHD risk in a third multivariate model that controlled for the effects of high density lipoprotein cholesterol to low density lipoprotein cholesterol ratio (standardized odds ratio = 0.57; 95% confidence interval 0.36-0.90). These findings are consistent with other evidence indicating that saturated fatty acids are directly correlated with CHD and that omega-3 polyunsaturated fatty acids are inversely correlated with CHD. Because these associations were present after adjustment for blood lipid levels, other mechanisms, such as a direct effect on blood clotting, may be involved.
To prospectively investigate the relation of plasma cholesterol ester (CE) and phospholipid (PL) fatty acid (FA) composition with incidence of coronary heart disease (CHD).
METHODS AND RESULTS:
3,591 white participants in the Minneapolis field center of the Atherosclerosis Risk in Communities Study, aged 45-64 years, were studied. Plasma FA composition of CEs and PLs was quantified using gas-liquid chromatography and expressed as percentage of total FAs. Incident CHD was identified during 10.7 years of follow-up. In both CE and PL fractions, the proportions of stearic (18:0) acid, dihomo-gamma-linolenic (20:3n6) acid and total saturated fatty acids (SFAs) were significantly higher while arachidonic (20:4n6) acid and total polyunsaturated fatty acids (PUFAs) were significantly lower among participants who developed incident CHD (n = 282). After adjusting for age, gender, smoking, alcohol drinking, sports activity, and non-FA dietary factors, the incidence of CHD was significantly and positively associated with the proportion of dihomo-gamma-linolenic acid but inversely associated with arachiadonic acid. The multiply-adjusted rate ratios (RRs) of CHD incidence for the highest versus the lowest quintile were 1.31 in CE and 1.44 in PL for dihomo-gamma-linolenic acid (p for trend: 0.05 and 0.017, respectively), 0.59 in CE and 0.65 in PL for arachidonic acid (p: 0.016 and 0.024, respectively). Also significantly and positively associated with incident CHD were PL stearic acid and CE linolenic (18:3n3) acid. Only a borderline significant positive association was observed for total SFAs in CE (multivariate RRs across quintiles: 1.00, 1.15, 1.40, 1.62, 1.32; p = 0.07). Total PUFAs or monounsaturated FA were not independently associated with CHD.
Our study found a weak positive association of SFAs with incident CHD. Our findings also confirm that FA metabolism in the body, such as the activity of delta-5 desaturase, which converts dihomo-gamma-linolenic acid to arachidonic acid, may affect the development of CHD.
Dietary Fatty Acids and Risk of Coronary Heart Disease in MenOur results suggest that SFA intake is not an independent risk factor for CHD, even in a population with higher ranges of SFA intake. In contrast, polyunsaturated fat intake was associated with lower risk of fatal CHD, whether replacing SFA, trans fat, or carbohydrates. Further investigation on the effect of monounsaturated fat on the CHD risk is warranted.