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source url Ketamine is emerging as a popular treatment for depression. New research suggests the drug acts like an opioid

 

Ketamine is emerging as a popular treatment for depression. New research suggests the drug acts like an opioid

  • Ketamine is emerging as a way to treat depression, but it appears to act like an opioid, Stanford researchers found.
  • Clinics are cropping up around the country where people receive ketamine infusions.
  • A handful of pharmaceutical companies, including Johnson & Johnson and Allergan, are using ketamine as inspiration for new prescription drugs to treat depression.
This is a vial of the animal tranquilizing drug ketamine hydrochloride, better known in the drug culture as "Special K."
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This is a vial of the animal tranquilizing drug ketamine hydrochloride, better known in the drug culture as “Special K.”

Ketamine is emerging as a way to treat depression, but it appears to act like an opioid — and it may carry similar risks, Stanford researchers found.

Clinics are cropping up around the country where people receive ketamine infusions. A handful of pharmaceutical companies are using ketamine as inspiration for new prescription drugs to treat depression. Yet the new research questions whether scientists know enough about chronic ketamine use to introduce it broadly.

The drug blocks NMDA receptors, which scientists think may treat depressive symptoms. Researchers wanted to test whether it was possible to elicit this reaction without activating the brain’s opioid receptors.

To block an opioid response, they gave participants naltrexone then infused them with ketamine. To compare that response with the normal response, they also gave participants a placebo before giving them the treatment.

Naltrexone so successfully blocked the anti-depressant effects of ketamine that researchers cancelled the study after the first interval because they felt it wasn’t ethical to continue it, said Dr. Nolan Williams, one of the study’s authors and a clinical assistant professor of psychiatry and behavioral sciences at Stanford University.

When patients took naltrexone, the opioid blocker, their symptoms did not improve, suggesting ketamine must first activate opioid receptors in order to treat depression, according to the study, published Wednesday in the American Journal of Psychiatry.

That’s not to say ketamine cannot be used occasionally, but it does raise questions about using it repeatedly over time, said Dr. Alan F. Schatzberg, co-author of the study and Stanford’s Kenneth T. Norris, Jr., professor of psychiatry and behavioral sciences. He likens it to opioid painkillers being an appropriate pain treatment when used once in the emergency room but posing problems, such as the risk of dependence, when used chronically.

“More studies need to be done to fully understand ketamine before it’s widely rolled out for long-term chronic use,” Schatzberg said.

Researchers planned on studying 30 adults but stopped enrolling patients once they decided combining ketamine and naltrexone was not only ineffective but also “noxious” for many participants. They tested a total of 12 people with both naltrexone and the placebo.

Of those 12, seven who received naltrexone experienced nausea after the ketamine infusion, compared to three in the placebo group. Two participants in each group also experienced vomiting.

Participants who received the placebo and ketamine treatment reported reduced depression symptoms. But those same participants did not see a decrease in depression symptoms after receiving ketamine and opioid-blocker naltrexone.

“We essentially blocked the mechanism for producing the anti-depressant effect, which were opioids,” said Williams.

The findings may have implications for clinics offering ketamine infusions and drug manufacturers trying to commercialize ketamine-like drugs.

Ketamine is meant to be used as an anesthetic. Since ketamine is currently not indicated to treat depression, insurance typically doesn’t cover the cost of infusions, so people tend to pay out of their own pocket. One session can run more than $500.

Meanwhile, drug giant Johnson & Johnson plans to seek approval from the Food and Drug Administration for its nasal spray esketamine this year after reporting positive results from a Phase 3 trial. Allergan plans to file its drug Rapastinel, which targets the NMDA receptors like ketamine, within the next two years. VistaGen Therapeutics is working on a similar drug.

In a statement, J&J said while the study reviewed ketamine and not esketamine, the findings “are difficult to interpret because of the study’s design.”

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Introduction

What comes to mind when you think of Ketamine? A drug of abuse? A horse tranquiliser? An anaesthetic agent? In reality it is all three. It usually has short-term hallucinogenic effects or causes a dissociative feeling (e.g. detachment from reality, sedation, or  inability to move). However, with frequent use over time it can cause permanent problems such as ‘ketamine bladder’, resulting in pain and difficulty passing urine.

What we already know

 

Ketamine’s effects are mainly mediated via NMDA (N-methyl-D-aspartate) receptor antagonism, although it is also an agonist at some opioid receptors and interacts with various other receptors, including noradrenaline, serotonin and muscarinic cholinergic receptors.

It is a class B illicit substance and was, in fact, upgraded from class C in June 2014 following a review of its harmful effects. Ketamine (either intramuscularly or intravenously) is licensed for use as an anaesthetic agent in children, young people and adults, but over the last few years interest has been growing in the role of Ketamine as an antidepressant agent. It is not currently licensed for this purpose.

here Areas of uncertainty

A study published in 2013 suggested that a single injected dose of Ketamine was associated with a rapid-onset antidepressant effect in patients with treatment-resistant depression (Murrough et al). The biggest challenge in terms of research with ketamine is that it remains tricky to compare against a placebo, given the fairly obvious side effects of taking a hallucinogenic drug, but this study compared Ketamine with Midazolam and this is probably the best comparator so far.

The following year, an open label study was published, which found similar antidepressant effects but a whole host of adverse effects were identified (Diamond et al), including anxiety and panic symptoms, increased suicidal ideation, vomiting, headaches and the anticipated feelings of detachment, confusion and dissociative symptoms.

There was a paucity of good quality information until, in 2015, a systematic review and meta-analysis of 21 studies  showed that single ketamine infusions produced a significant anti-depressant effect for up to seven days. Beyond this time, there was no evidence to suggest a prolonged effect.

What’s in the pipeline

There is some evidence to suggest that Ketamine may also work for Post-Traumatic Stress Disorder and Obsessive Compulsive Disorder. Another proposed use for Ketamine (currently being researched at the University of Manchester) is as an adjunct for Electroconvulsive Therapy (ECT), potentially minimizing the cognitive impairments experienced post-ECT.

Ketamine remains one of the most promising new treatments for depression, both unipolar and bipolar, but it is not without its problems. Requiring specialist referral and a stay in hospital overnight for a single dose clearly has financial and logistical implications far beyond those of antidepressant tablets with a stronger evidence base behind them. We also need more information about safety and adverse effects, before it can be introduced to a wider market.

References

Coyle, C. M. and Laws, K. R. (2015), The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum. Psychopharmacol Clin Exp. [Abstract]

Diamond PR, Farmery AD, Atkinson S, Haldar J, Williams N, Cowen PJ, Geddes JR and McShane R. Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic (PDF). J Psychopharmacol, 0269881114527361, first published on April 3, 2014. [PDF]

Murrough, J.W.; Iosifescu, D.V.; Chang, L.C.; Al Jurdi, R.K.; Green, C.E.; Perez, A.M. et al. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression; a two-site randomized controlled trial. Am J Psychiatry, 170, 1134-1142. [Abstract]

The antidepressant effects of ketamine are confirmed by a new systematic review and meta-analysis

shutterstock_18453376In recent times, few drugs have caused more excitement among clinical researchers than ketamine. It’s well known for its role in anaesthesia and veterinary surgery (“horse tranquilizer”), as well as its illicit use, but progress has been ongoing for about 15 years to repurpose it as an antidepressant.

As a consequence, many new studies are published every month that evaluate to what extent ketamine lives up to its promise as a new antidepressant drug (Aan Het Rot, Zarate, Charney, & Mathew, 2012). To make sense of the flood of new information, naturally intrigued mental elves clearly need researchers to provide timely updates of the current state of knowledge. To this end, Coyle and Laws (2015) have recently published an extensive systematic review and the first meta-analysis that summarises the latest, methodologically sound research.

The key questions of interest to these researchers were:

  • Does ketamine have an immediate effect in reducing depressive symptoms?
  • Are the antidepressant effects of ketamine sustained over time?
  • Are repeat infusions more effective in reducing depressive symptoms?
  • Do primary diagnosis and experimental design moderate the impact of ketamine on depressive symptoms?
  • Do men and women experience differences in the antidepressant effect of ketamine?

This review looked at how well the effects of ketamine are maintained over

This review looked at how well the effects of ketamine are maintained over 4 hours, 24 hours, 7 days and 12-14 days.

Methods

The authors followed PRISMA guidelines and scanned all relevant medical databases for studies assessing the antidepressant potential of ketamine in patients with major depressive disorder (MDD) and bipolar disorder (BD). To evaluate possible methodological factors and design variables, the authors also specifically assessed whether studies were: repeat/single infusion, diagnosis, open-label/participant-blind infusion, pre-post/placebo-controlled design and patients’ sex.

Effect sizes were calculated either relative to placebo or relative to baseline, in case no control group was provided. To correct for bias in small studies, a Hedge’s g procedure with random effects was used. Statistical heterogeneity, publication bias and moderator variables were assessed to have an idea of other variables that might influence the reported antidepressant potential of ketamine. Statistical heterogeneity among studies was assessed using I² values, with values above 50% generally representing substantial heterogeneity.

Results

In total, 21 studies enrolling 437 patients receiving ketamine were identified that satisfied inclusion criteria:

  • 17 were single infusion studies and the majority reported data collected at 4h (11) and 24h (13) after ketamine treatment
  • 6 studies had follow-up for 7 days
  • 4 studies had follow-up for 12-14 days

In general, there are grounds to assume publication bias for single infusion studies at 4h and 24h.

Of the 21 included studies, 2 were judged to be at a high risk of bias, 13 medium risk and 6 low risk of bias.

  • In general, ketamine had a large statistical effect on depressive symptoms that was comparable across all time points
  • Effect sizes were significantly larger for repeat than single infusion at 4 h, 24 h and 7 days
  • For single infusion studies, effect sizes were large and significant at 4 h, 24 h and 7 days
  • The overall pooled effect sizes for single and repeated ketamine infusions found no difference at any time point, suggesting that the antidepressant effects of ketamine are maintained for at least 12-14 days

table3

Moderator analyses suggest that responsiveness to ketamine may vary according to diagnosis. Specifically, while ketamine produced moderate to large effects in both MDD and BD patients, the effect of a single infusion was significantly larger in MDD than BD after 24h. On the other hand, after 7 days, this pattern reversed and ketamine showed higher efficacy in BD patients. However, the small number of studies makes it tricky to draw any conclusions.

In addition, single-infusion pre-post comparisons did not differ in effect size estimation from placebo-controlled designs except for at 12-14 days, where only one study was available. In a similar vein, there were no effect size differences between single infusion studies with open-label and blinded infusions.

Of note, the meta-analysis found the percentage of males in the group was positively associated with ketamine’s antidepressant effects after 7 days, although this finding warrants replication with more data points.

There's huge room for improvement in the primary research, but this analysis shows ketamine in a promising light as an antidepressant.

There’s plenty of room for improvement in the primary research, but this meta-analysis shows ketamine in a promising light as an antidepressant.

Conclusions

The authors conclude:

Single ketamine infusions elicit a significant anti-depressant effect from 4h to 7days; the small number of studies at 12-14 days post infusion failed to reach significance. Results suggest a discrepancy in peak response time depending upon primary diagnosis – 24 h for MDD and 7 days for BD. The majority of published studies have used pre-post comparison; further placebo-controlled studies would help to clarify the effect of ketamine over time.

Limitations

This meta-analysis suffers from several limitations that are inherent in the available studies:

  • For one, there were only four studies that assessed the effect of repeated ketamine infusions, which is a shame given that maintenance of antidepressant effects is one of the key drawbacks of rapidly acting interventions
  • In addition, the authors note that their results suggest publication bias, which may be taken to indicate that several negative findings have not been published and thus could not be included in this meta-analysis
  • Also, more information about adverse effects would have been useful, especially to evaluate whether ketamine can be safely applied in a broader clinical context

Summary

This is the first meta-analysis to evaluate ketamine’s antidepressant effects. For single infusion specifically, ketamine exerts large antidepressant effects in MDD as well as BD patients that seem to last at least 7 days, while too few studies are available beyond this time point.

It’s noteworthy that the effect sizes did not differ between time points, which indicates that the effect of a single infusion remains relatively stable in the short-term. While repeated infusions were shown to provide higher effects than single infusions at least for the first week, more studies are needed to corroborate the supremacy of repeated treatment.

Before ketamine can become a clinically viable treatment option, however, this review makes it clear that more methodologically refined studies (especially RCTs with adequate placebo controls) need to be conducted. With this in mind, researchers should take these findings as an incitement to action!

High quality

High quality placebo controlled trials are needed to drive forward progress in this field.

Links

Primary paper

Coyle, C. M. and Laws, K. R. (2015), The use of ketamine as an antidepressant: a systematic review and meta-analysisHum. Psychopharmacol Clin Exp, doi: 10.1002/hup.2475. [PubMed abstract]

Other references

Aan Het Rot, M., Zarate, C. a, Charney, D. S., & Mathew, S. J. (2012). Ketamine for depression: where do we go from here? Biological Psychiatry72(7), 537–47. doi:10.1016/j.biopsych.2012.05.003

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The use of Ketamine for depression has been increasingly utilized and found effective for suicidal thoughts and treatment -resistant depression. The article below discusses the use of Ketamine in other mood disorders and the manner with which it is given:

 

Agrowing number of small clinical trials have demonstrated that subanesthetic doses of ketamine can produce antidepressant effects in patients with mood disorders who have demonstrated refractoriness to standard therapies.1 Patients in these trials have been diagnosed with major depressive disorder and bipolar disorder, and the sample sizes have ranged from 8 to 99. While there is broad agreement that ketamine-like drugs hold considerable promise as novel antidepressant agents, the increasing number of clinicians from a variety of medical specialties offering ketamine as an off-label treatment for psychiatric disorders2 has raised concern.

Although ketamine has been approved by the US Food and Drug Administration (FDA) as an anesthetic for more than 45 years, there remain concerns about the safety of repeated ketamine dosing. These concerns stem in part from reports of cognitive impairment and bladder dysfunction associated with repeated administration of the drug in rodent models and in humans with ketamine use disorder. Furthermore, concerns of spawning a substantial increase in iatrogenic ketamine use disorder related to wider use of ketamine for treating mental health disorders have led some to suggest more restricted use until additional data are available.

However, the lack of patent protection surrounding the use of racemic ketamine hydrochloride as a treatment for mood disorders makes it unlikely that larger phase 3 trials required for FDA consideration or standard postmarketing surveillance studies addressing issues of longer-term safety and effectiveness will ever be completed. In light of these facts, the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments issued a consensus statement on the off-label use of ketamine for the treatment of mood disorders.3 This Viewpoint summarizes a number of important issues related to the clinical use of ketamine for the treatment of psychiatric disorders addressed in the consensus statement and provides suggestions for addressing remaining concerns.

Who Should Be Considered for Ketamine Treatment?

There was strong agreement among the contributors to the consensus that appropriate patient selection is a critical and necessary factor in optimizing the risk/benefit ratio of this novel treatment strategy. This requires a comprehensive evaluation and thorough consideration of the individual’s potential risks and benefits, considering the medical, psychological, and social factors specific to each patient. Considering the limited longer-term safety and efficacy data, only patients who have not responded to adequate trials of more standard antidepressant treatments should be candidates. Agreement was also reached that patients should be informed of the extent of the existing evidence regarding the use of ketamine in the treatment of psychiatric disorders before they provide consent to treatment. This should include acknowledgment of the relative dearth of published data on any diagnosis other than major depressive episodes, the limited evidence of long-term effectiveness, the possible or likely need for repeated administrations to maintain response, and the concerns regarding cognitive impairment, cystitis, and abuse liability.

Clinical Experience, Training, and Treatment Setting

No published guidelines exist delineating required clinician training prior to providing subanesthetic doses of ketamine as a treatment. Considering the delivery regimen most commonly used in published research protocols (0.5 mg/kg infused intravenously over 40 minutes) typically results in peak ketamine serum levels that are an order of magnitude below the peak levels used for anesthesia,4 it does not seem reasonable to impose the same training requirements as would be used in the case of ketamine anesthesia. However, even subanesthetic doses of ketamine can induce potentially concerning transient elevations in both heart rate and blood pressure.5 In addition, patients may also experience prominent psychoactive effects (such as perceptual and cognitive disturbances, derealization, and depersonalization) that can persist for 30 to 120 minutes following infusion cessation.

In consideration of these risks, the consensus statement recommended that, at a minimum, clinicians who administer ketamine be prepared to manage both cardiovascular and behavioral events should such arise, and suggested certification in Advanced Cardiac Life Support for clinicians delivering the treatment. The consensus statement also suggests that ketamine be provided by a clinician who can administer Drug Enforcement Agency Schedule III medications (in most states, this is a licensed physician with an MD or DO degree). The treatment facility should have a means of providing basic cardiac and respiratory monitoring as well as an established plan for providing stabilization and rapid transfer of patients with sustained alterations in cardiac functioning.

Dose and Delivery Procedure

Most evidence available to date has supported the use of 0.5-mg/kg ketamine hydrochloride given intravenously over 40 minutes. Comparatively little research has been published on other doses, routes of administration, or infusion durations. The only available randomized clinical data comparing various doses come from 2 small trials of 99 and 71 patients that suggest both lower and higher ketamine doses (0.1-1.0 mg/kg) may have some efficacy. Nevertheless, it should be noted that in both studies, the more commonly used 0.5-mg/kg dose was at least numerically more efficacious.6,7 Furthermore, the increased efficacy of the 0.5-mg/kg dose may be more pronounced in patients with severe depression compared with lower doses.7 However, lower doses do appear to have few associated adverse events. Thus, because of limited data, it is not possible to clarify the relative benefits and risks of doses other than 0.5 mg/kg delivered intravenously over 40 minutes.

To ensure patient safety, site-specific standard operating procedures should be developed and should include assessments of baseline vital signs, confirmation of preprocedural informed consent, criteria for acceptable baseline vital signs prior to initiating treatment, and criteria for prematurely stopping an infusion. Posttreatment assessments should confirm that each patient returns to a mental state that will allow for a safe return to the current living situation and a responsible adult should be available to transport the patient home if treatments are done on an outpatient basis.

Course of Treatment Planning

The only existing study to date examining dosing frequency suggests that dosing thrice weekly is no better than twice weekly induction dosing, although this evidence comes from a comparatively small (n = 68) randomized clinical trial.5 While some clinicians have reported more frequent dosing strategies,2 there is currently no published evidence to support the benefits of this practice over lower-frequency treatments.

Most published data supporting the use of ketamine as a treatment for mood disorders are based on trials that have followed up patients for just 1 week after a single administration of the drug.1 While a few small trials (7 trials with sample sizes ranging from 9 to 68) have demonstrated the relative safety of repeated infusions (4-6 total infusions over a couple of weeks), there is very little published data on the efficacy and safety of longer-term use. Most of these repeated dosing trials have shown that the majority of benefit experienced by patients occurs within the first 2 weeks of treatment. Hence, it may be reasonable to discontinue treatment after 2 weeks if no meaningful benefit is achieved.

As most trials to date suggest that a short course of ketamine does not usually provide long-lasting benefits to patients with a chronic disease, many clinicians currently offer maintenance ketamine treatment.2 However, there is insufficient evidence to meaningfully inform long-term treatment with ketamine. Considering the liability of the potential for abuse as well as concerns for cognitive impairment and cystitis associated with chronic high-frequency exposure, it is reasonable to suggest that clinicians limit the administration to the minimum effective dosing frequency and use recurring assessments of cognition, bladder functioning, and substance use when long-term treatment is provided until more information on the longer-term safety is available. Moreover, during this early stage of clinical development, the consensus statement strongly cautions against the practice of take-home, self-administration of ketamine.

Conclusions

While the discovery of ketamine’s robust and rapid-acting antidepressant effects has appropriately led to considerable enthusiasm among some clinicians and considerable hope among some patients, this enthusiasm for this promising treatment should be coupled with caution given the limitations of the existing knowledge base and the potential adverse effects of long-term treatment. However, considering the tremendous individual and societal burden of mood disorders, the high percentage of patients that do not achieve satisfactory responses from the currently available approved treatments, and the recent evidence of rising rates of suicide, expedited research into this potentially transformative treatment is needed. Several ongoing studies (such as NCT01945047NCT03113968, and NCT00088699) are attempting to address these knowledge gaps and enrollment in these trials should be encouraged when possible. In addition to the standard randomized clinical trials, the creation of a registry of patients receiving ketamine off-label as a treatment for mood disorders could serve as an efficient way to learn more about the longer-term effectiveness and safety of the treatment and could be beneficial in guiding the rational use of the treatment.

References

1.

Newport  DJ, Carpenter  LL, McDonald  WM, Potash  JB, Tohen  M, Nemeroff  CB; APA Council of Research Task Force on Novel Biomarkers and Treatments.  Ketamine and other NMDA antagonists.  Am J Psychiatry. 2015;172(10):950-966.PubMedGoogle ScholarCrossref

2.

Wilkinson  ST, Toprak  M, Turner  MS, Levine  SP, Katz  RB, Sanacora  G.  A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders.  Am J Psychiatry. 2017;174(7):695-696.PubMedGoogle ScholarCrossref

3.

Sanacora  G, Frye  MA, McDonald  W,  et al; American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments.  A consensus statement on the use of ketamine in the treatment of mood disorders.  JAMA Psychiatry. 2017;74(4):399-405.PubMedGoogle ScholarCrossref

4.

Vuyk  J, Sitsen  E, Reekers  M. Intravenous anesthetics. In: Miller  RD, ed.  Miller’s Anesthesia. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015:821-863.

5.

Singh  JB, Fedgchin  M, Daly  EJ,  et al.  A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression.  Am J Psychiatry. 2016;173(8):816-826.PubMedGoogle ScholarCrossref

6.

Fava  M, Freeman  MP, Flynn  M,  et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression. Presented at: Annual Meeting of the American Society of Clinical Psychopharmacology; May 30, 2017; Miami, Florida.

7.

Su  TP, Chen  MH, Li  CT,  et al.  Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression [published online May 11, 2017].  Neuropsychopharmacology. doi:10.1038/npp.2017.94PubMedGoogle Scholar

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders

Gerard Sanacora, MD, PhD1Mark A. Frye, MD2William McDonald, MD3et alSanjay J. Mathew, MD4,5Mason S. Turner, MD6Alan F. Schatzberg, MD7Paul Summergrad, MD8Charles B. Nemeroff, MD, PhD9; for the American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments
JAMA Psychiatry. 2017;74(4):399-405. doi:10.1001/jamapsychiatry.2017.0080

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders

Abstract

Importance  Several studies now provide evidence of ketamine hydrochloride’s ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.

Observations  This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.

Conclusions and Relevance  The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.

 

Introduction

 

The American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments found that the data from 7 published placebo-controlled, double-blind, randomized clinical studies on ketamine hydrochloride infusion therapy in the treatment of depression comprising 147 treated patients provide “compelling evidence that the antidepressant effects of ketamine infusion are both rapid and robust, albeit transient.”1(p958) Reports of ketamine’s unique antidepressant effects, combined with frequent media coverage promulgating the potential benefits of ketamine treatment, have generated substantial interest and optimism among patients, families, patient advocacy groups, and clinicians alike. This interest has led to a rapidly escalating demand for clinical access to ketamine treatment and an increasing number of clinicians willing to provide it. However, many in the field suggest that caution should be used with this approach, as the numbers of patients included in these published studies and case series remain relatively small (the eTable in the Supplement compares other recently developed treatments), and ketamine treatment for mood disorders has not been tested in larger-scale clinical trials to demonstrate its durability and safety over time.2,3 Moreover, the treatment approach has not been subject to the scrutiny of a US Food and Drug Administration review or approval for an on-label psychiatric indication, and, despite more than 45 years of clinical experience with ketamine as an anesthetic agent, there are no postmarketing surveillance data on the use of ketamine for any psychiatric indication to provide information on its safety and effectiveness.

 

The relatively unique nature of this situation presents an urgent need for some guidance on the issues surrounding the use of ketamine treatment in mood disorders. This review by the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments Subgroup on Treatment Recommendations for Clinical Use of Ketamine is intended to complement the recent American Psychiatric Association meta-analysis1 and other recent reviews410 and aims to provide an overview and expert clinical opinion of the critical issues and considerations associated with the off-label use of ketamine treatment for mood disorders. Because relatively limited high-quality, published information on this topic exists, to our knowledge, this report is not intended to serve as a standard, guideline, clinical policy, or absolute requirement. The main intent of the report is to highlight the current state of the field and the critical issues to be considered when contemplating the use of ketamine for treatment-resistant depression. Use of this report cannot guarantee any specific outcome and is not endorsed or promulgated as policy of the American Psychiatric Association.

 

Patient Selection

 

There are no clearly established indications for the use of ketamine in the treatment of psychiatric disorders. However, the selection of appropriate patients for ketamine treatment requires consideration of the risks and benefits of the treatment in the context of the patient’s severity of depression, duration of current episode, previous treatment history, and urgency for treatment. To date, the strongest data supporting ketamine’s clinical benefit in psychiatric disorders are in the treatment of major depressive episodes without psychotic features associated with major depressive disorder.1,11 Even these data are limited by the fact that most of those studies evaluated efficacy only during the first week following a single infusion of ketamine. However, emerging studies suggest that repeated dosing can extend the duration of effect for at least several weeks.12,13 Although some limited data on the use of ketamine in treating other psychiatric diagnoses exist (eBox 1 in the Supplement), we do not believe there are sufficient data to provide a meaningful review of the assessment of risks and benefits of ketamine use in these other disorders at present.

 

In addition to diagnostic considerations, appropriate patient selection requires an assessment of other medical, psychological, or social factors that may alter the risk to benefit ratio of the treatment and affect the patient’s capacity to provide informed consent. For these reasons, we recommend that each patient undergo a thorough pretreatment evaluation process (Table)1417 that assesses several relevant features of the patient’s past and current medical and psychiatric condition before initiating ketamine treatment. We also recommend that an informed consent process be completed during this evaluation. Rationale for the suggestions listed in the Table are provided in eBox 1 in the Supplement.

 

Clinician Experience and Training

 

There are considerable differences in the experience and clinical expertise of the clinicians currently administering ketamine to patients for the treatment of mood disorders. At present, there are no published guidelines or recommendations outlining the specific training requirements that clinicians should complete before administering doses of ketamine that are lower than those used in anesthesia. In attempting to balance the needs for treatment availability and patient safety, one must consider the information available regarding the use of ketamine at the relevant dose range in similar patient populations to formulate an advisory on clinical credentialing for ketamine administration for the treatment of mood disorders.

 

The peak plasma ketamine hydrochloride concentrations of 70 to 200 ng/mL seen with the typical antidepressant dose of 0.5 mg/kg delivered intravenously (IV) during 40 minutes (0.5 mg/kg per 40 minutes IV) do not produce general anesthetic effects. The concentrations are well below the peak plasma ketamine hydrochloride concentrations generally used for surgical anesthesia (2000-3000 ng/mL) and below the concentrations associated with awakening from ketamine hydrochloride anesthesia (500-1000 ng/mL).1820 Reporting on 833 ketamine infusions in healthy individuals resulting in peak plasma ketamine concentrations in the same general range as those achieved with a dose of 0.5 mg/kg per 40 minutes IV, Perry et al21 found 3 individuals who became nonresponsive to verbal stimuli, but all remained medically stable during the infusion and none required any form of respiratory assistance. A second, more recent study reported no persistent medical complications or significant changes in oxygen saturation among 84 otherwise healthy patients with depression who received a total of 205 infusions of ketamine hydrochloride, 0.5 mg/kg per 40 minutes IV.9 However, transient mean (SD) peak increases in systolic (19.6 [12.8] mm Hg) and diastolic (13.4 [9.8] mm Hg) blood pressure were reported during the infusions, with blood pressure levels exceeding 180/100 mm Hg or heart rates exceeding 110 beats per minute in approximately 30% of the patients treated. A single serious adverse cardiovascular-related event was reported in this study (0.49% of infusions), but it was considered to be attributable to a vasovagal episode following venipuncture for a blood draw, and it resolved without complications.

 

The data available from these studies and other case reports in the literature suggest that the dose of ketamine hydrochloride typically used in the treatment of mood disorders (0.5 mg/kg per 40 minutes IV) does not appear to have significant effects on the respiratory status of healthy individuals or patients with depression who are otherwise generally medically healthy. However, ketamine treatment could have meaningful effects on blood pressure and heart rate for some patients. Considering the potential risks associated with ketamine hydrochloride administration at the dose of 0.5 mg/kg per 40 minutes IV, it is recommended that clinicians delivering the treatment be prepared to manage potential cardiovascular events should they occur. Based on this information, we suggest that a licensed clinician who can administer a Drug Enforcement Administration Schedule III medication (in most states this is an MD or DO with appropriate licensing) with Advanced Cardiac Life Support certification should provide the treatments.

 

Because it is also possible for patients to experience prominent transient dissociative or even psychotomimetic effects while being treated with ketamine,22 clinicians should also be familiar with behavioral management of patients with marked mental status changes and be prepared to treat any emergency behavioral situations. Furthermore, it is suggested that an on-site clinician be available and able to evaluate the patient for potential behavioral risks, including suicidal ideation, before discharge to home. Finally, treating clinicians should be able to ensure that rapid follow-up evaluations of patients’ psychiatric symptoms can be provided as needed.

 

In addition to the minimal general training requirements, it is also recommended that clinicians develop some level of experience with the specific method of ketamine administration before performing the procedure independently. Precise delineation of required experience and documentation of this experience should be based on local community standards of practice and/or clinical practice committees. Reports such as the Statement on Granting Privileges for Administration of Moderate Sedation to Practitioners Who Are Not Anesthesia Professionals, published by the American Society of Anesthesiologists,23 can be used to inform the development of these standards.

 

Treatment Setting

 

Although the administration of ketamine at peak plasma concentrations similar to those produced by a dose of 0.5 mg/kg per 40 minutes IV has proven to be relatively safe to date, the potentially concerning acute effects on cardiovascular function and behavior suggest that the clinical setting should provide sufficient means of monitoring the patients and providing immediate care if necessary. Although there are relatively low levels of evidence to support the use of any specific monitoring methods in reducing the risks of ketamine treatment with doses that are lower than those used in anesthesia, it should be expected that such a facility have a means of monitoring basic cardiovascular (electrocardiogram, blood pressure) and respiratory (oxygen saturation or end-tidal CO2) function. It should also be expected that there would be measures in place to rapidly address and stabilize a patient if an event should arise. These measures would include a means of delivering oxygen to patients with reduced respiratory function, medication, and, if indicated, restraints to manage potentially dangerous behavioral symptoms. Moreover, there should be an established plan to rapidly address any sustained alterations in cardiovascular function, such as providing advanced cardiac life support or transfer to a hospital setting capable of caring for acute cardiovascular events. Patients deemed at higher risk for complications based on pretreatment evaluation should be treated at a facility that is appropriately equipped and staffed to manage any cardiovascular or respiratory events that may occur.

 

Medication Delivery

 

Dose

 

Most clinical trials and case reports available in the literature have used the ketamine hydrochloride dose of 0.5 mg/kg per 40 minutes IV that was cited in the original report by Berman et al.24 Limited information is available regarding the use of different routes of delivery and doses of ketamine. A meta-analysis of 6 trials assessing the effects of the standard dose of 0.5 mg/kg per 40 minutes IV and 3 trials assessing very low doses of ketamine hydrochloride (50-mg intranasal spray, 0.1-0.4 mg/kg IV, and 0.1-0.5 mg/kg IV intramuscularly or subcutaneously) reported that the dose of 0.5 mg/kg per 40 minutes IV appears to be more effective than very low doses in reducing the severity of depression.4 However, there is substantial heterogeneity in the design of the clinical trials, and the total number of participants included in that analysis is very few, markedly limiting the ability to draw any firm conclusions from this report.

 

Although there is now a growing number of reports examining the effects of various doses and rates of ketamine infusion, including studies showing lower doses and reduced infusion rates2527 to be effective and studies showing higher doses and extended infusion rates28,29 to have clinical benefit, at present we believe that insufficient information was provided in those studies to allow any meaningful analysis of any specific dose or route of treatment compared with the standard dose of 0.5 mg/kg per 40 minutes IV. Considering the lower-level evidence for doses and routes of administration other than 0.5 mg/kg per 40 minutes IV, if alternative doses are being used, that information should be presented to the patient during the informed consent process, and appropriate precautions should be made in managing any increased risk associated with the changes in ketamine administration. However, the use of alternative doses and routes of administration could be appropriate for individual patients under specific conditions.

 

One example of a rationale for dose adjustment is related to the dosing of ketamine for patients with a high body mass index (calculated as weight in kilograms divided by height in meters squared). The fact that greater hemodynamic changes were observed in patients with a body mass index of 30 or higher who were receiving a dose of 0.5 mg/kg per 40 minutes9suggests that adjusting the ketamine dosing to ideal body weight (using the person’s calculated ideal body weight and not actual body weight to determine dosing) may be an appropriate step to help ensure safety for patients with a body mass index of 30 or higher. However, there is currently very limited information supporting this approach.

 

Delivery Procedure

 

To help best ensure patient safety and to minimize risks, it is strongly advised that site-specific standard operating procedures be developed and followed for the delivery of ketamine treatments for major depressive episodes. The standard operating procedure should contain predosing considerations covering the following: (1) confirmation of preprocedural evaluation and informed consent; (2) assessment of baseline vital signs, including blood pressure, heart rate, and oxygen saturation or end-tidal CO2; (3) criteria for acceptable baseline vital signs before initiation of medication delivery (eBox 2 in the Supplement); and (4) incorporation of a “time-out” procedure in which the name of the patient and correct dosing parameters are confirmed.

Supplement

 

Standard operating procedures should also include specifically defined ongoing assessments of patients’ physiological and mental status during the infusion process, including the following: (1) assessment of respiratory status (ie, oxygen saturation or end-tidal CO2); (2) assessment of cardiovascular function (blood pressure and heart rate, reported on a regular basis); (3) assessment of the level of consciousness (ie, Modified Observer’s Assessment of Alertness/Sedation Scale30) or other documented assessment of responsiveness; and (4) delineation of criteria for stopping the infusion (eBox 3 in the Supplement) and a clear plan for managing cardiovascular or behavioral events during treatment.

 

Immediate posttreatment evaluations, assessments, and management should ensure that the patient has returned to a level of function that will allow for safe return to his or her current living environment. This assessment should include documentation of return to both baseline physiological measures and mental status. It is also critical to ensure that a responsible adult is available to transport the patient home if the treatment is being administered on an outpatient basis. Recommendations regarding driving and use of heavy machinery, as well as use of concomitant medications, drugs, or alcohol, should also be reviewed before discharge. It is also important to review follow-up procedures and ensure that the patient has a means of rapidly contacting an appropriately trained clinician if necessary.

 

Follow-up and Assessments

 

Efficacy Measures of Short-term Repeated Administration

 

The existing data surrounding the benefits of repeated infusions of ketamine remain limited.1,11 Although an increasing number of small case series evaluate the efficacy of repeated ketamine administration for the treatment of major depressive episodes, there is a very small number of randomized clinical trials in the literature.1 The lack of clinical trials in this area makes it difficult to provide suggestions on the frequency and duration of treatment with even moderate levels of confidence. Most studies and case reports published to date on this topic have examined the effects of less than 1 month of treatment.12,26,3134

 

A recent randomized, placebo-controlled clinical trial (using saline as the placebo) of 68 patients with treatment-resistant major depressive disorder examined the efficacy of ketamine, 0.5 mg/kg per 40 minutes IV, both 2 and 3 times weekly for up to 2 weeks and found both dosing regimens to be nearly equally efficacious (change in mean [SD] Montgomery-Åsberg Depression Rating Scale total score for ketamine 2 times weekly, –18.4 [12.0] vs placebo, –5.7 [10.2]; and ketamine 3 times weekly, –17.7 [7.3] vs placebo, –3.1 [5.7]).13 After 2 weeks of treatment, patients treated with ketamine 2 times weekly showed a 69% rate of response and 37.5% rate of remission vs placebo, at 15% and 7.7%, respectively, and those treated with ketamine 3 times weekly had a 53.8% rate of response and 23.1% rate of remission vs placebo, at 6% and 0%, respectively. In the ensuing open-label phase of the study, patients were allowed to continue with active medication at the dose frequency they were originally assigned for an additional 2-week period. At the end of 4 weeks of treatment, the 13 patients who received ketamine 2 times weekly and continued to receive the additional 2 weeks of treatment had a mean 27-point reduction in the Montgomery-Åsberg Depression Rating Scale score compared with a 23-point decrease for the 13 patients who received ketamine 3 times weekly. Although this was clearly not a definitive study, it is the best evidence currently available, to our knowledge, to suggest that twice-weekly dosing is as efficacious as more frequent dosing for a period of up to 4 weeks. In general, most of the available reports describing the effects of repeated treatments showed the largest benefits occurring early in the course of treatment, but some reports did show some cumulative benefit of continued treatment.31

 

Very limited data exist to suggest a clear point of determining the futility of treatment, but there are a few reports of patients responding after more than 3 infusions. Based on the limited data available, patients should be monitored closely using a rating instrument to assess clinical change to better reevaluate the risk to benefit ratio of continued treatment. In addition, only 1 report suggests that an increased dose of ketamine (beyond 0.5 mg/kg per 40 minutes) may lead to a response to treatment in patients who had previously not responded.28 Equally few data are available to suggest a standard number of treatments that should be administered to optimize longer-term benefit of the treatment.

 

Efficacy of Longer-term Repeated Administration

 

To our knowledge, there are extremely limited published data on the longer-term effectiveness and safety of ketamine treatment in mood disorders. This literature is confined to a few case series that do not allow us to make a meaningful statement about the longer-term use of ketamine.35,36 Several clinics providing such treatments are currently using a 2- or 3-week course of ketamine delivered 2 or 3 times per week, followed by a taper period and/or continued treatments based on empirically determined duration of responses for each patient. However, there remain no published data that clearly support this practice, and it is strongly recommended that the relative benefit of each ketamine infusion be considered in light of the potential risks associated with longer-term exposure to ketamine and the lack of published evidence for prolonged efficacy with ongoing administration. The scarcity of this information is one of the major drawbacks to be considered before initiating ketamine therapy for patients with mood disorders and should be discussed with the patient before beginning treatment.

 

Safety Measures and Continuation of Treatment

 

Based on the known or suspected risks of cognitive impairment37 and cystitis38 associated with chronic high-frequency use of ketamine and the known substance abuse liability of the drug, assessments of cognitive function, urinary discomfort, and substance use39 should be considered if repeated administrations are provided (eBox 4 in the Supplement).

 

Considering the known potential for abuse of ketamine40 and recent reports of abuse of prescribed ketamine for the treatment of depression,41 clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder. Close clinical follow-up with intermittent urine toxicology screening for drugs of abuse and inquiries about attempts to receive additional ketamine treatments at other treatment centers should be implemented when clinical suspicion of ketamine abuse is present. Moreover, the number and frequency of treatments should be limited to the minimum necessary to achieve clinical response. Considering the evidence suggesting that the mechanism of action requires some delayed physiological effect to the treatment and does not appear to require sustained blood concentrations of the drug to be present, there is no evidence to support the practice of frequent ketamine administration. The previously mentioned report showing twice-weekly dosing to be at least as effective as dosing 3 times a week13 for up to 4 weeks appears to support this idea instead of more frequent dosing schedules.

 

At this point of early clinical development, we strongly advise against the prescription of at-home self-administration of ketamine; it remains prudent to have all doses administered with medical supervision until more safety information obtained under controlled situations can be collected. Discontinuation of ketamine treatment is recommended if the dosing cannot be spaced out to a minimum administration of 1 dose per week by the second month of treatment. The goal remains to eventually taper and discontinue treatment until more long-term safety data can be collected.

 

Future Directions

 

The rapid onset of robust, transient antidepressant effects associated with ketamine infusions has generated much excitement and hope for patients with refractory mood disorders and the clinicians who treat them. However, it is necessary to recognize the major gaps that remain in our knowledge about the longer-term efficacy and safety of ketamine infusions. Future research is needed to address these unanswered questions and concerns. Although economic factors make it unlikely that large-scale, pivotal phase 3 clinical trials of racemic ketamine will ever be completed, there are several studies with federal and private foundation funding aiming to address some of these issues. It is imperative that clinicians and patients continue to consider enrollment in these studies when contemplating ketamine treatment of a mood disorder. It is only through these standardized clinical trials that we will be able to collect the data necessary to answer some of the crucial questions pertaining to the efficacy and safety of the drug. A second means of adding to the knowledge base is to develop a coordinated system of data collection on all patients receiving ketamine for the treatment of mood disorders. After such a registry is created, all clinicians providing ketamine treatment should consider participation.

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Revisiting the Hallucinogenic Potential of Ketamine

 

LIPSKIY/SHUTTERSTOCK.COM; WITHTHESEHANDS/SHUTTERSTOCK.COM

A Case Built on Current Research Findings

Ketamine has caused quite a stir in psychiatric practice. Sub-anesthetic administrations of ketamine have been shown to markedly improve symptoms of depression and anxiety.1 While the growing off-label use of ketamine speaks to the need for novel approaches to psychiatric care and treatment-resistant illness, it also presents an ethical dilemma, wherein widespread adoption has once again leaped ahead of scientific understanding.

The current literature suggests that therapeutic effects of ketamine involve modulation of glutamate neurotransmission, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor potentiation, downstream influences on neurotrophic signaling cascades and neuroplasticity, and functional changes in assorted neural networks. Additional work is necessary to clarify the importance and reliability of these biological findings.

Another arc to the ketamine story dates back to a decades-old era of psychedelic research and search for medications with transformative power. Indeed, although primarily conceptualized today as a dissociative anesthetic, ketamine has also been classified more broadly as a hallucinogen. Hallucinogens function by various pharmacological mechanisms of action but exhibit similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes.

Current biological theories involving ketamine’s antidepressant effect may be inseparable from these non-ordinary experiences of consciousness, but we can only know the answers to questions we ask. Here we examine findings from contemporary research that hint at the unexplored hallucinogenic potential of ketamine and considerations for future investigation.

There has been a resurgence of interest in hallucinogenic psychedelics (eg, psilocybin, lysergic acid diethylamide (LSD), mescaline, N,N-Dimethyltryptamine (DMT)) and entactogens (eg, 3, 4-methylenedioxymethamphetamine [MDMA]) in psychiatric research, which are hypothesized to achieve clinical benefit due to, in part, experiences of altered consciousness and fundamental shifts in mental frameworks.2

These drugs have been associated with cognitive states of enduring personal importance and have been compared with mystical experiences that might emerge over the ordinary course of life and carry sacred or spiritual meaning. Furthermore, these experiences may powerfully influence existential concepts of self, including moral values, self-identity, and purpose. There is converging evidence that these psychedelic effects are mediated in part by activity at 5HT-2A receptors. Ketamine may induce alterations in consciousness and personal frameworks similar to those achieved by serotonergic psychedelics while also sharing a common glutamatergic pathway of drug effect.3,4 However, there has been little investigation into how such changes might mediate the therapeutic potential of ketamine.

Preliminary data suggest that ketamine produces meaningful, transformative experiences that may help patients accept healthier values, behaviors, and beliefs related to abstinence from drugs and alcohol.5,6 Other evidence suggests that dose-related mystical-type experiences mediate the effects of ketamine on motivation to quit in cocaine-dependent research volunteers.7Few recent studies have examined whether ketamine’s hallucinogenic properties are implicated in antidepressant effects; however, psychiatric vulnerabilities to depression plausibly involve an existential dimension. This dimension includes depressive symptoms of hopelessness, guilt, and suicidality, which appear to be ketamine-sensitive.8

The evidence

Given the paucity of modern literature exploring the psychedelic and mystical properties of ketamine in depression, more widespread data on psychotomimetic and dissociative effects of ketamine provide some initial groundwork. Berman and collegeagues9 and Zarate and colleagues10 suggested that the antidepressant effects of ketamine (0.5 mg/kg over 40 min) were disconnected from ketamine-induced psychotomimetic symptoms. The antidepressant effects, measured by the Hamilton Depression Rating Scale (HDRS), were significant even after positive symptoms on the Brief Psychiatric Rating Scale (BPRS) returned to baseline. However, it was also noted that initial changes in BPRS positive symptom scales from baseline trended to predict a greater decrease in HDRS scores within a day of treatment with ketamine.

A small study further demonstrated a substantial relationship between psychotomimetic effects 30 minutes after ketamine administration (0.54mg/kg over 30 min) as measured by BPRS and antidepressant effects in the following week.11 A larger study involving 108 patients found that dissociation measured by the Clinician Administered Dissociative States Scale (CADDS) at 40 minutes was associated with HDRS score improvement at 230 minutes and 7 days after infusion.12 Although no relationship between initial BPRS positive subscale scores and antidepressant effect was found, a correlation between CADSS and BPRS scores was found at 40 minutes postinfusion.

In a small study by Valentine and colleagues,13 the proposed correlation between ketamine-induced dissociation and antidepressant efficacy was not observed. However, a larger analysis found that greater intra-infusion dissociation as measured by CADDS was one of the strongest predictors of extended antidepressant response.14 Both of these studies utilized a single 0.5 mg/kg ketamine infusion delivered over 40 minutes.

Further investigation is needed, but there is an emerging rationale for a connection between the psychotomimetic or dissociative effects of ketamine and its antidepressant efficacy. Perhaps the experience of these effects simply un-blinds patients as to whether they are receiving ketamine or placebo in randomized trials; it may also be that such symptoms are only a “side effect” of ketamine’s mechanism of action. However, it is also worth considering that the psychotomimetic or dissociative effects associated with ketamine treatment are markers or mediators of subjective experiences of potential therapeutic value seen with other hallucinogenic agents.

Recommended dosing

The recommended doses of ketamine for anesthetic induction are typically 1 to 4.5mg/kg IV and 6.5 to 13 mg/kg IM, with alternate, off-label recommendations for 0.5 to 2 mg/kg IV and 4 to 10 mg/kg IM, primarily in the context of adjuvant drug use. For use in depression, ketamine is most commonly administered at a sub-anesthetic dose of 0.5mg/kg IV across 40 minutes.

Interestingly, in a study of electroconvulsive therapy (ECT) and anesthetic induction with either a near-anesthetic dose of IV ketamine (0.8mg/kg) alone, sub-anesthetic ketamine (0.5mg/kg) plus propofol (0.8mg/kg), or propofol alone (0.8mg/kg), predicted a more rapid antidepressant effect and a higher remission rate than propofol use. The near-anesthetic dose of ketamine was associated with superior antidepressant effects than the mixed, sub-anesthetic dose.15

In a study of ketamine alongside psychotherapy for heroin addiction, Krupitsky and colleagues6compared the effects of 2 doses of ketamine (0.2 and 2.0 mg/kg IM) and found that only the higher dose was associated with a “full psychedelic experience” as measured by the Hallucinogen Rating Scale (HRS). The lower dose was considered a “sub-psychedelic” active placebo, but was nonetheless associated with some positive drug effects: patients were still affected by their experiences and considered them useful and therapeutic. The high dose group ultimately experienced higher rates of abstinence, greater effect on emotional attitudes related to abstinence, and lower rates of relapse and drug craving than the low dose group. Both doses resulted in post-treatment reductions in measures of depression and anxiety; there were no significant differences between the groups.

Similarly, Dakwar and colleagues7 compared the effects of 0.41 mg/kg and 0.71 mg/kg doses of IV ketamine given to cocaine-dependent patients. Dose-dependent mystical-type effects as measured by Hood’s Mysticism Scale (HMS) were seen as well as a relationship between HMS scores and the motivation to quit cocaine 24 hours post-infusion.

A different study involving a lower dose of intramuscular (IM) ketamine did not generate the same mystical-type phenomena.16 Perhaps these results highlight the importance of calibrating dosing and delivery. Clements and colleagues17 demonstrated that ketamine had reduced bioavailability with IM administration compared with IV administration. Taken together, these findings support the idea that positive treatment outcomes for ketamine may be dose-dependent and its psychoactive effects are based on delivery parameters.

Limitation

One criticism of ketamine has been its short duration of antidepressant effect, with benefits peaking at 24 hours post-infusion and generally subsiding by 72 hours. The most promising approach to this challenge thus far seems to be the strategy of repeated-dose ketamine infusions, which have observed extended time-to-relapse and increased rates of antidepressant response.18

If ketamine’s therapeutic effect is indeed mediated by psychoactive experience, it may be that repeated dosing of ketamine improves outcomes by increasing opportunities for personally meaningful events to occur. One caveat is that some studies have shown repeated dosing to be associated with fewer dissociative symptoms over time—at first glance this suggests that the antidepressant value of serial ketamine administration might be independent of hallucinogenic effects.

While this requires further investigation, it is also important to consider other interpretations of that evidence: that acclimation to altered states of consciousness may contribute to recall bias, that experimental protocols that frame dissociative symptoms as a “side effect” or “adverse event” may lead to underreporting if overall patient experiences of ketamine are positive, or even that the benefit of repeated dosing may be less related to cumulative drug effect than other factors, such as repeated interactions with care providers or increased opportunities for reflection and synthesis.

One study of repeated infusions demonstrated that antidepressant response very early in the course of treatment strongly predicted subsequent response; conversely, a lack of rapid response was a poor prognostic indicator for improvement after additional infusions. Whether positive early responses to ketamine are mediated by psychological factors, biological susceptibility, or both: it is necessary to clarify these factors in shaping sustainable strategies for treatment.

A cautious approach also seems imperative given evidence that ketamine demonstrates agonist activity at μ-opioid receptors and dopaminergic effects that may confer acute relief of depressive symptoms but also greater risk for positive drug reinforcement and dependence. With further insight into psychological responses mediated by ketamine, it may be that a therapy-based framework for ketamine administration optimizes treatment efficacy and sustainability, while also minimizing unnecessary drug exposure, adverse effects of chronic use, and dependency risk.

Further study needed

In one study, long-term abstinence in persons who were substance dependent was achieved with Ketamine Psychedelic Therapy (KPT), which incorporates 1 or 2 sessions of ketamine-facilitated existential reappraisal into an existential psychotherapy.6 Additional exploration would be needed to determine which therapeutic approaches most beneficially augment ketamine treatment and minimize risks for harm. Nevertheless, a more holistic approach to ketamine as a treatment modality may be better suited to recreate the marked, persistent effects of MDMA in patients with PTSD. For example, in one study sustained symptom reductions were achieved with 12 weeks of psychotherapy but with limited MDMA exposures of only three 8-hour sessions.19

Another area that requires further investigation is how a patient’s past history might shape psychoactive responses. These personal and quite variable histories have been explored for some hallucinogenic agents but minimally for ketamine. The expectations and personal experiences of the individual user along with the external environment of use have been identified as critical factors in influencing subjective drug effects—coined “set” and “setting,” respectively—and are now considered well-established elements of human hallucinogen research.20

Therapies aimed at the pharmacological production of a transformative experience may depend on factors such as patient personality structure, preparation for treatment, emotional activation before drug intake, treatment context, and perceived quality of the experience. Given the unique psychological risks of hallucinogen administration, it is recommended that clinicians screen for personal or family histories of psychotic or other severe psychiatric disorders prior to treatment. Clinicians are also encouraged to facilitate careful patient preparation for sessions, provide a safe physical environment for treatment administration, and allow for interpersonal support during sessions. These and other insights from hallucinogenic research might valuably inform treatment protocols for ketamine administration.

Ketamine is uniquely poised to make a tremendous impact on psychiatric care, even redefining boundaries for patients with variations in depressive disorders that were once thought to be “treatment resistant.” Our synthesis of this emerging and old literature points to the unexplored hallucinogenic potential of ketamine. By further understanding the desirable psychoactive effects of ketamine, clinicians can build on initial treatment successes and maximize patient successes.

Future directions for research include:

• Further investigating the relationship between ketamine-induced psychotomimetic and dissociative effects and treatment efficacy

• Clarifying the connection between these effects and potentially desirable hallucinogenic experiences

• Exploring the therapeutic value of such elicited experiences

• Revisiting dosing strategies that account for existential phenomena and looking beyond dissociation as simply being an “adverse event”

• Incorporating psychotherapy-based frameworks into ongoing investigation

• Assessing set and setting factors that may shape treatment responses

Some answers and clues are likely to be found in the forgotten works of older psychedelic research. Agents like ketamine can exert their greatest therapeutic effect in the afterglow of profound alterations of consciousness, revealing a propensity for growth and healing that has not been evident to the suffering, depressed patient. Wherever the journey takes us, it is exactly the right time to bring together all the strands—brain and mind, old and new, caution and thrill—in assembling the unfinished story of ketamine.

 

References:

1. Feifel D. Breaking sad: unleashing the breakthrough potential of ketamine’s rapid antidepressant effects. Drug Dev Res. 2016;77;489-494.

2. Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacol (Berl). 2006;187:268-283, 292.

3. Perry EB, Cramer JA, Cho HS, et al. Psychiatric safety of ketamine in psychopharmacology research. Psychopharmacol (Berl). 2007;192:253-260.

4. Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci. 2010;11:642-651.

5. Jansen KLR. Ketamine: Dreams and Realities. Sarasota, FL: Multidisciplinary Association for Psychedelic Studies; 2001.

6. Krupitsky E, Burakov A, Romanova T, et al. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. J Subst Abuse Treat. 2002;23:273-283.

7. Dakwar E, Levin F, Foltin RW, et al. The effects of sub-anesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine dependent research volunteers. Biol Psychiatry. 2014;76:40-46.

8. Mathew SJ, Shah A, Lapidus K, et al. Ketamine for treatment-resistant unipolar depression: current evidence. CNS Drugs. 2012;26:189-204.

9. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.

10. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.

11. Sos P, Kirova M, Novak T, et al. Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol Lett. 2013;34:287-293.

12. Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord. 2014;159:56-61.

13. Valentine GW, Mason GF, Gomez R, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res. 2011;191:122-127.

14. Pennybaker SJ, Niciu MJ, Luckenbaugh DA, Zarate CA. Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion. J Affect Disord. 2017;208:560-566.

15. Zhong X, He H, Zhang C, et al. Mood and neuropsychological effects of different doses of ketamine in electroconvulsive therapy for treatment-resistant depression. J Affect Disord. 2016;201:124-130.

16. Lofwall MR, Griffiths RR, Mintzer MZ. Cognitive and subjective acute dose effects of intramuscular ketamine in healthy adults. Exp Clin Psychopharmacol. 2006;14:439-449.

17. Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharma Sci. 1982;71:539-542.

18. Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74:250-256.

19. Mithoefer, M. C. et al. Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. J Psychopharmacol. 2013;27:28-39.

20. Leary T, Litwin GH, Metzner R. Reactions to psilocybin administered in a supportive environment. J Nerv Ment Dis. 1963;137:561-573.

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Magnesium is essential for our health. It is a key cofactor for our energy regulation, and in plants it is the center of the chlorphyll molecule. Low magnesium in people is associated with depression. Among the treatments we provide at the IV Medical Center is Ketamine infusions. In the process of our treatments, we assess patients for toher medical conditions that may lead to refractory depression and low magnesium is one of them.

 

 

Ketamine, an anesthetic and street drug known as “Special K” has garnered a lot of attention for it’s ability, in some, to relieve the symptoms of very severe depression in a matter of minutes. A recent study has demonstrated how it might work, but before you go signing up for a clinical trial (and there are currently many going on in the US), it’s important to understand the downsides to the drug. One major problem is that the effects wear off, usually within 10 days, leaving you just as depressed as before. It can cause urinary incontinence, bladder problems, addiction, and, with chronic use, it can worsen mental health problems, causing more depression, anxiety, and panic attacks.

Ketamine seems to have a remarkable, short term ability to heal the synapses injured by chronic stress. However, anything that acts that quickly and successfully usually has a long-term cost. All powerfully addictive drugs work on our own natural receptors and neurons. Cocaine, for example, causes immediate racing euphoria by inhibiting the natural neurotransmitter dopamine from being recycled, leaving bunches of dopamine in the synaptic cleft. In the very short term, you feel great. In the long term, you tax the system by driving the neurotransmitter system far out of balance in an aggressive way.

Nicotine has a similar effect on the alpha-7 nicotinic receptor. It activates it in a pleasing way, but unfortunately desensitizes the receptor so much that only nicotine will keep it firing. A nutrient found in foods such as egg yolks called choline activates the same receptor, but without desensitizing it.  Long term, regular ingestion of choline keeps the receptor functional and happy, helping with certain brain tasks. Long term, regular use of nicotine activates the receptor but forces you to take more nicotine to keep the receptor working, leaving you foggy-headed and less sharp if you go without cigarettes.

So is there a less dramatic, “natural” version of ketamine, something we can safely ingest every day, but might be a little depleted in our modern diets? Nothing taken in physiologic amounts would reverse a depression in half an hour like ketamine, but could another chemical we find in food and mineral water help with resilience to stress, synaptic repair, and make us more resistant to depression and anxiety symptoms? Sure—that chemical is the mineral magnesium. Magnesium, like ketamine, acts as an antagonist to the NMDA receptor, which means it is a counter to glutamate, the major excitatory neurotransmitter in the brain. The exact mechanisms are complex, but both ketamine and magnesium seem to help glutamate do its job, activating the receptor, without damaging the receptor with too much activation, which, chronically, leads to excitotoxicity, synaptic degradation, inflammation, and even cell death.

One of the exciting things about ketamine is that it works in some people with severe treatment resistant depression who have failed the traditional therapies. Treatment-resistant individuals tend to have lower intracellular magnesium levels than normal (1). Ketamine and magnesium may also work synergistically, complementing each other. Ketamine leads to an increase of intracellular magnesium, and ketamine will reverse the normally seen magnesium decreases after brain trauma (2). There is some evidence also that more standard antidepressant medications, such as imipramine, work in part by reversing the magnesium-depleting effects of chronic stress, suggesting that adding magnesium supplementation to standard antidepressant regimens might help the medications work better (at least in rodents) (3).

It’s great to see an interesting compound like ketamine be taken seriously and thoroughly studied for its action in serious, resistant depression. Ultimately its usefulness may be limited to hospitalized patients who can be closely monitored for the side effects, and who also may benefit the most from the quick mechanism of action, while the longer term risks may be outweighed by the short term benefit in such a critical, serious situation. I would love to see a much safer compound, the mineral magnesium, be studied as an adjunct treatment.

In the mean time, magnesium supplementation is generally safe for most folks with normal kidney function. Many folks eating a normal Western Diethave a low intake of the mineral (4). Those with bowel obstructions, very slow heart rate, or dangerously low blood pressure should not take it. Magnesium can interfere with the absorption of certain medicines (digoxin, nitrofurantoin, bisphosphanates, and some anti malaria drugs). Here are some excellent food sources of magnesium (though remember that both nuts and grains have phytates, which bind minerals, so the magnesium you absorb may not be quite as much as the magnesium you ingest.) Magnesium is also available in many mineral waters.

 

Lets digress over Choline. Choline has impact on decreasing schizophrenia in the children of mother’s who supplement the right amount during pregnancy:

Recently in the American Journal of Psychiatrya new paper was published tying nutrient supplementation in pregnant women to positive changes in the brains of their offspring. One of the nutrients that may be less predominant in our modern diets than in traditional diets is the phospholipid known as choline. Phospholipids are exceedingly important for brain development and neuron signaling.

In the current study, 100 pregnant women were randomized to receiving a daily choline supplement (equivalent to the amount of choline found in 3 large eggs) or placebo. After the babies were born, the choline babies continued to get a supplement equal to 100mg of choline daily (the institutes of medicine recommend total daily choline in infants to be 125mg daily), and at measurements of “cerebral inhibition” were taken at about one month and three months of age. Cerebral inhibition is a term used to describe the ability of the brain to tune out a stimulus that happens over and over. For example, if you are trying to work, and someone is running a jackhammer on the street outside, if you have intact cerebral inhibition, your brain will respond less and less to the sound of the jackhammer as it continues. Presumably this change would allow you to focus on more important things, such as the work at hand.

Source: http://www.flickr.com/photos/anniemole/5268772776/sizes/m/

In some brain disorders, such as schizophrenia, cerebral inhibition is impaired. For someone with schizophrenia, the signal from the jackhammer would be just as strong the second and the third and the seventh and the eighth times. You can imagine how you might be affected if you couldn’t tune anything out, if your brain was constantly taking in more stimulation and unable to sort through what was necessarily important or not. It could be this lack of cerebral inhibition (which begins with brain development in utero and early infancy) is one of the central causes of developing schizophrenia later on. The brain, so overwhelmed with stimuli, stops making sense of it, leading to psychosis and eventually the degeneration of neurons.

Cerebral inhibition is typically measured by a test called the p50 evoked potential. Electrodes are placed on the scalp, and then the subject is exposed to a sensory stimulus, in this case, paired sounds. With intact cerebral inhibition, the second time the brain processes the sound, the wave amplitude of the auditory evoked potential 50 milliseconds after the sound will be much less than the first time. (Go to this image from the American Journal of Psychiatry to see what the waveforms look like in healthy controls and subjects with schizophrenia.

P50 evoked potential abnormalities can be seen in infants, and genes that are associated with a higher risk of schizophrenia are also associated with these abnormal evoked potential tests. Choline is known to cross the placenta and help with the brain development of certain receptors that normalize cerebral inhibition. In the study of pregnant women receiving choline supplements, 76% of the infants whose mothers got choline had normal p50 evoked potential tests at age one month. Only 43% of the infants of the mothers who received placebo had tests consistent with intact cerebral inhibition. In addition, a gene known as CHRNA7 correlated with diminished cerebral inhibition in the placebo group of infants, but not in the choline group. That means that it is possible (though there is way too little data to know) the choline supplementation could reduce the risk of schizophrenia in these infants. The ScienceDaily write up of the study can be found here.

Schizophrenia risk is higher in the offspring of malnourished mothers. There is also a known gene that reduces choline levels that is associated with a higher risk of schizophrenia. Choline is also sequestered in the mother’s liver during trauma, anxiety, or depression, depriving the fetus. Measures of developmental delay and other developmental problems are also associated with later risk of schizophrenia.

Nicotine activates but also profoundly desensitizes the same receptor that choline seems to protect and activate (the alpha-7 nicotinic receptor). 90% of people with schizophrenia smoke, and smoking normalizes p50 evoked potential tests is schizophrenia. Smoking in mothers has been associated with poorer infant cerebral inhibition and later childhood behavioral problems, whereas choline has only been shown to be beneficial for brain development. One difference between the two compounds (among many!) is that choline does not desensitize the alpha-7 nicotinic receptor at all, leaving it active so it can play its presumed role in helping with intact cerebral inhibition.

While choline supplementation is the interest of researchers, I’m more interested in having pregnant women eat their meat and egg yolks, the best sources of choline in the diet. Egg yolks are jam packed with great nutrients for the brain, not only choline, but also B vitamins and other fatty acids important for nerve growth. Bananas also have more choline than you would expect for a fruit. Choline levels in the diet have fallen recently with folks restricting their egg and organ meat consumption. These traditional foods have some important nutrients that we don’t want to skimp on in our diets.

 

Choline supplementation during pregnancy presents a new approach to schizophrenia prevention

Choline, an essential nutrient similar to the B vitamin and found in foods such as liver, muscle meats, fish, nuts and eggs, when given as a dietary supplement in the last two trimesters of pregnancy and in early infancy, is showing a lower rate of physiological schizophrenic risk factors in infants 33 days old. The study breaks new ground both in its potentially therapeutic findings and in its strategy to target markers of schizophrenia long before the illness itself actually appears. Choline is also being studied for potential benefits in liver disease, including chronic hepatitis and cirrhosis, depression, memory loss, Alzheimer’s disease and dementia, and certain types of seizures.

Robert Freedman, MD, professor and chairman of the Department of Psychiatry, University of Colorado School of Medicine and one of the study’s authors and Editor of The American Journal of Psychiatry, points out, “Genes associated with schizophrenia are common, so prevention has to be applied to the entire population, and it has to be safe. Basic research indicates that choline supplementation during pregnancy facilitates cognitive functioning in offspring. Our finding that it ameliorates some of the pathophysiology associated with risk for schizophrenia now requires longer-term follow-up to assess whether it decreases risk for the later development of illness as well.”

Normally, the brain responds fully to an initial clicking sound but inhibits its response to a second click that follows immediately. In schizophrenia patients, deficient inhibition is common and is related to poor sensory filtering and familial transmission of schizophrenia risk. Since schizophrenia does not usually appear until adolescence, this trait — measurable in infancy — was chosen to represent the illness.

Half the healthy pregnant women in this study took 3,600 milligrams of phosphatidylcholine each morning and 2,700 milligrams each evening; the other half took placebo. After delivery, their infants received 100 milligrams of phosphatidylcholine per day or placebo. Eighty-six percent of infants exposed to pre- and postnatal choline supplementation, compared to 43% of unexposed infants, inhibited the response to repeated sounds, as measured with EEG sensors placed on the baby’s head during sleep.

 


Journal Reference:

  1. Randal G. Ross et al. Perinatal Choline Effects on Neonatal Pathophysiology Related to Later Schizophrenia RiskAmerican Journal of Psychiatry, 2013; DOI: 10.1176/appi.ajp.2012.12070940
  2. Perinatal Choline Effects on Neonatal Pathophysiology Related to Later Schizophrenia Risk

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Ketamine, magnesium and major depression–from pharmacology to pathophysiology and back.

Ketamine, magnesium and major depression e From pharmacology to pathophysiology and back

Abstract

The glutamatergic mechanism of antidepressant treatments is now in the center of research to overcome the limitations of monoamine-based approaches. There are several unresolved issues. For the action of the model compound, ketamine, NMDA-receptor block, AMPA-receptor activation and BDNF release appear to be involved in a mechanism, which leads to synaptic sprouting and strengthened synaptic connections. The link to the pathophysiology of depression is not clear. An overlooked connection is the role of magnesium, which acts as physiological NMDA-receptor antagonist: 1. There is overlap between the actions of ketamine with that of high doses of magnesium in animal models, finally leading to synaptic sprouting. 2. Magnesium and ketamine lead to synaptic strengthening, as measured by an increase in slow wave sleep in humans. 3. Pathophysiological mechanisms, which have been identified as risk factors for depression, lead to a reduction of (intracellular) magnesium. These are neuroendocrine changes (increased cortisol and aldosterone) and diabetes mellitus as well as Mg(2+) deficiency. 4. Patients with therapy refractory depression appear to have lower CNS Mg(2+) levels in comparison to health controls. 5. Experimental Mg(2+) depletion leads to depression- and anxiety like behavior in animal models. 6. Ketamine, directly or indirectly via non-NMDA glutamate receptor activation, acts to increase brain Mg(2+) levels. Similar effects have been observed with other classes of antidepressants. 7. Depressed patients with low Mg(2+) levels tend to be therapy refractory. Accordingly, administration of Mg(2+) either alone or in combination with standard antidepressants acts synergistically on depression like behavior in animal models.

CONCLUSION:

On the basis of the potential pathophysiological role of Mg(2+)-regulation, it may be possible to predict the action of ketamine and of related compounds based on Mg(2+) levels. Furthermore, screening for compounds to increase neuronal Mg(2+) concentration could be a promising instrument to identify new classes of antidepressants. Overall, any discussion of the glutamatergic system in affective disorders should consider the role of Mg(2+)

 

So back to the magnesium and Ketamine issue: As above, Low magnesium seems to be present in individuals who are depressed and have sleeping disorders. The magnesium is not the type measured by standard blood tests as most magnesium is intracellular. Magnesium may play an important role by antagomizing the NMDA receptors as does Ketamine. Our deficient diets in Magnesium may be increasing our rates of depression!

Magnesium as the original Chill Pill

Source: http://www.flickr.com/photos/derekskey/3219004793/

Magnesium is a vital nutrient that is often deficient in modern diets. Our ancient ancestors would have had a ready supply from organ meats, seafood, mineral water, and even swimming in the ocean, but modern soils can be depleted of minerals and magnesium is removed from water during routine municipal treatment. The current RDA for adults is between 320 and 420mg daily, and the average US intake is around 250mg daily.

Does it matter if we are a little bit deficient? Well, magnesium plays an important role in biochemical reactions all over your body.  It is involved in a lot of cell transport activities, in addition to helping cells make energy aerobically or anaerobically. Your bones are a major reservoir for magnesium, and magnesium is the counter-ion for calcium and potassium in muscle cells, including the heart. If your magnesium is too low, you can experience muscle cramps, arrythmias, and even sudden death. Ion regulation is everything with respect to how muscles contract and nerves send signals. In the brain, potassium and sodium balance each other. In the heart and other muscles, magnesium pulls some of the load.

That doesn’t mean that magnesium is unimportant in the brain. Au contraire!In fact, there is an intriguing article entitled Rapid recovery from major depression using magnesium treatment, published in Medical Hypothesis in 2006. Medical Hypothesis seems like a great way to get rampant (but referenced) speculation into the PubMed database. Fortunately, I don’t need to publish in Medical Hypothesis, as I can engage in such speculation in my blog, readily accessible to Google. Anyway, this article was written by George and Karen Eby, who seem to run a nutrition research facility out of an office warehouse in Austin, Texas – and it has a lot of interesting information about our essential mineral magnesium.

Magnesium is an old home remedy for all that ails you, including “anxiety, apathy, depression, headaches, insecurity, irritability, restlessness, talkativeness, and sulkiness.” In 1968, Wacker and Parisi reported that magnesium deficiency could cause depression, behavioral disturbances, headaches, muscle cramps, seizures, ataxia, psychosis, and irritability – all reversible with magnesium repletion.

Stress is the bad guy here, in addition to our woeful magnesium deficient diets. As is the case with other minerals such as zinc, stress causes us to waste our magnesium like crazy – I’ll explain a bit more about why we do that in a minute.

Let’s look at Eby’s case studies from his paper:

A 59 y/o “hypomanic-depressive male”, with a long history of treatable mild depression, developed anxiety, suicidal thoughts, and insomnia after a year of extreme personal stress and bad diet (“fast food”). Lithium and a number of antidepressants did nothing for him. 300mg magnesium glycinate (and later taurinate) was given with every meal. His sleep was immediately restored, and his anxiety and depression were greatly reduced, though he sometimes needed to wake up in the middle of the night to take a magnesium pill to keep his “feeling of wellness.” A 500mg calcium pill would cause depression within one hour, extinguished by the ingestion of 400mg magnesium.

A 23 year-old woman with a previous traumatic brain injury became depressed after extreme stress with work, a diet of fast food, “constant noise,” and poor academic performance. After one week of magnesium treatment, she became free of depression, and her short term memory and IQ returned.

A 35 year-old woman with a history of post-partum depression was pregnant with her fourth child. She took 200mg magnesium glycinate with each meal. She did not develop any complications of pregnancy and did not have depression with her fourth child, who was “healthy, full weight, and quiet.”

A 40 year-old “irritable, anxious, extremely talkative, moderately depressed” smoking, alchohol-drinkingcocaine using male took 125mg magnesium taurinate at each meal and bedtime, and found his symptoms were gone within a week, and his cravings for tobacco, cocaine, and alcoholdisappeared. His “ravenous appetite was supressed, and … beneficial weight loss ensued.”

Eby has the same question about the history of depression that I do – why is depression increasing? His answer is magnesium deficiency. Prior to the development of widespread grain refining capability, whole grains were a decent source of magnesium (though phytic acid in grains will bind minerals such as magnesium, so the amount you eat in whole grains will generally be more than the amount you absorb). Average American intake in 1905 was 400mg daily, and only 1% of Americans had depression prior to the age of 75. In 1955, white bread (nearly devoid of magnesium) was the norm, and 6% of Americans had depression before the age of 24. In addition, eating too much calcium interferes with the absorption of magnesium, setting the stage for magnesium deficiency.

Beyond Eby’s interesting set of case studies are a number of other studies linking the effects of this mineral to mental health and the stress response system. When you start to untangle the effects of magnesium in the nervous system, you touch upon nearly every single biological mechanism for depression. The epidemiological studies (1) and some controlled trials (2)(3) seem to confirm that most of us are at least moderately deficient in magnesium. The animal models are promising (4). If you have healthy kidneys, magnesium supplementation is safe and generally well-tolerated (up to a point)(5), and many of the formulations are quite inexpensive. Yet there is a woeful lack of well-designed, decent-sized randomized controlled trials for using magnesium supplementation as a treatment or even adjunctive treatment for various psychiatric disorders.

Let’s look at the mechanisms first. Magnesium hangs out in the synapse between two neurons along with calcium and glutamate. If you recall, calcium and glutamate are excitatory, and in excess, toxic. They activate the NMDA receptor. Magnesium can sit on the NMDA receptor without activating it, like a guard at the gate. Therefore, if we are deficient in magnesium, there’s no guard. Calcium and glutamate can activate the receptor like there is no tomorrow. In the long term, this damages the neurons, eventually leading to cell death. In the brain, that is not an easy situation to reverse or remedy.

And then there is the stress-diathesis model of depression, which is the generally accepted theory that chronic stress leads to excess cortisol, which eventually damages the hippocampus of the brain, leading to impaired negative feedback and thus ongoing stress and depression and neurotoxicity badness. Murck tells us that magnesium seems to act on many levels in the hormonal axis and regulation of the stress response. Magnesium can suppress the ability of the hippocampus to stimulate the ultimate release of stress hormone, it can reduce the release of ACTH (the hormone that tells your adrenal glands to get in gear and pump out that cortisol and adrenaline), and it can reduce the responsiveness of the adrenal glands to ACTH. In addition, magnesium can act at the blood brain barrier to prevent the entrance of stress hormones into the brain. All these reasons are why I call magnesium “the original chill pill.”

If the above links aren’t enough to pique your interest, depression is associated with systemic inflammation and a cell-mediated immune response. Turns out, so is magnesium deficiency. In addition, animal models show that sufficient magnesium seems to protect the brain from depression and anxiety after traumatic brain injury (6), and that the antidepressants desipramine and St. John’s Wort (hypericum perforatum) seem to protect the mice from the toxic effects of magnesium deficiency and its relationship to anxious and depressed behaviors (4).

The overall levels of magnesium in the body are hard to measure. Most of our body’s magnesium is stored in the bones, the rest in the cells, and a very small amount is roaming free in the blood. One would speculate that various mechanisms would allow us to recover some needed magnesium from the intracellular space or the bones if we had plenty on hand, which most of us probably don’t. Serum levels may be nearly useless in telling us about our full-body magnesium availability, and studies of levels and depression, schizophrenia, PMS, and anxiety have been all over the place (7). There is some observational evidence that the Mg to Ca ratio may be a better clue. Secondly, the best sources of magnesium in the normal Western diet are whole grains (though again, phytates in grains will interfere with absorption), beans, leafy green veggies, and nuts. These happen to be some of the same sources as folate, and folate depletion is linked with depression, so it may be a confounding factor in the epidemiological studies.

Finally, magnesium is sequestered and wasted via the urine in times of stress. I’m speculating here, but in a hunter-gatherer immediate stress sort of situation, maybe we needed our neurons to fire on all cylinders and our stress hormones to rock and roll through the body in order for us to survive. Presumably we survived or didn’t, and then the stressor was removed, and our paleolithic diets had plenty of magnesium to replace that which went missing. However, it may not be overall magnesium deficiency causing depression and exaggerated stress response – it may just be all that chronic stress, and magnesium deficiency is a biomarker for chronic stress. But it doesn’t hurt to replete one’s magnesium to face the modern world, and at least the relationships should be studied thoroughly. Depression is hugely expensive and debilitating. If we could alleviate some of that burden with enough mineral water… we should know whether that is a reasonable proposition.

As I mentioned before, there are only a few controlled trials of magnesium supplementation and psychiatric disorders. A couple covered premenstrual dysphoria, cravings, and other symptoms (8)(9). Another small study showed some improvement with magnesium supplementation in chronic fatigue syndrome (10). Two open-label studies showed some benefit in mania (11)(12). There is another paper that postulates that magnesium deficiency could exacerbate the symptoms of schizophrenia. However, there is nothing definitive. Which is, of course, quite troubling. How many billions of dollars have we spent on drug research for depression, bipolar disorder, and schizophrenia, when here is a cheap and plausibly helpful natural remedy that hasn’t been properly studied?

So everyone get out there and take some magnesium already!  Whew.  Well, just a few more things to keep in mind before you jump in.

There are some safety considerations with respect to magnesium supplementation. If you have normal kidney function, you do not have myasthenia gravis, bowel obstruction, or bradycardia, you should be able to supplement without too many worries. In addition, magnesium interferes with the absorption of certain pharmaceuticals, including dixogin, nitrofurantoin, bisphosphanates, and some antimalaria drugs. Magnesium can reduce the efficacy of chloropromazine, oral anticoagnulants, and the quinolone and tetracycline classes of antibiotics.

Magnesium oxide is the cheapest readily available formulation, as well as magnesium citrate, which is more likely to cause diarrhea in excess. (In fact, magnesium is a great remedy for constipation). The oxide is not particularly bioavailable, but the studies I’ve referenced above suggest that you can top yourself off after about a month of daily supplementation. Those with short bowels (typically due to surgery that removes a large section of bowel) may want to supplement instead with magnesium oil. You can also put some Epsom salts in your bath. In addition to diarrhea, magnesium can cause sedation, and symptoms of magnesium toxicity (again, quite unlikely if your kidneys are in good shape) are low blood pressure, confusion, arrythmia, muscle weakness, and fatigue. Magnesium is taken up by the same transporter as calcium and zinc, so they can fight with each other for absorption. Jaminet and Jaminet recommend total daily levels (between food and supplements) of 400-800mg. Most people can safely supplement with 200-350mg daily without any problems (again, don’t proceed without a doctor’s supervision if you have known kidney disease or if you are elderly).

People looking for good (but not all paleo) food sources can go here (also a good link for more information on the other formulations of magnesium – there are many!), here, and here.

 

Following are some foods and the amount of magnesium in them:[23]

 

MAGNESIUM  

Magnesium Webpage as below

 

Summary

Magnesium plays important roles in the structure and the function of the human body. The adult human body contains about 25 grams of magnesium. Over 60% of all the magnesium in the body is found in the skeleton, about 27% is found in muscle, 6% to 7% is found in other cells, and less than 1% is found outside of cells (1).

Function

Magnesium is involved in more than 300 essential metabolic reactions, some of which are discussed below (2).

Energy production

The metabolism of carbohydrates and fats to produce energy requires numerous magnesium-dependent chemical reactions. Magnesium is required by the adenosine triphosphate (ATP)-synthesizing protein in mitochondria. ATP, the molecule that provides energy for almost all metabolic processes, exists primarily as a complex with magnesium (MgATP)(3).

Synthesis of essential molecules

Magnesium is required for a number of steps during synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. Several enzymes participating in the synthesis of carbohydrates and lipids require magnesium for their activity. Glutathione, an important antioxidant, requires magnesium for its synthesis (3).

Structural roles

Magnesium plays a structural role in bone, cell membranes, and chromosomes (3).

Ion transport across cell membranes

Magnesium is required for the active transport of ions like potassium and calcium across cell membranes. Through its role in ion transport systems, magnesium affects the conduction of nerve impulses, muscle contraction, and normal heart rhythm (3).

Cell signaling

Cell signaling requires MgATP for the phosphorylation of proteins and the formation of the cell-signaling molecule, cyclic adenosine monophosphate (cAMP). cAMP is involved in many processes, including the secretion of parathyroid hormone (PTH) from the parathyroid glands (see the articles on Vitamin D and Calcium for additional discussions regarding the role of PTH) (3).

Cell migration

Calcium and magnesium levels in the fluid surrounding cells affect the migration of a number of different cell types. Such effects on cell migration may be important in wound healing (3).

Nutrient interactions

Zinc

High doses of zinc in supplemental form apparently interfere with the absorption of magnesium. One study reported that zinc supplements of 142 mg/day in healthy adult males significantly decreased magnesium absorption and disrupted magnesium balance (the difference between magnesium intake and magnesium loss) (4).

Fiber

Large increases in the intake of dietary fiber have been found to decrease magnesium utilization in experimental studies. However, the extent to which dietary fiber affects magnesium nutritional status in individuals with a varied diet outside the laboratory is not clear (2, 3).

Protein

Dietary protein may affect magnesium absorption. One study in adolescent boys found that magnesium absorption was lower when protein intake was less than 30 grams/day, and higher protein intakes (93 grams/day vs. 43 grams/day) were associated with improved magnesium absorption in adolescents (5).

Vitamin D and calcium

The active form of vitamin D (calcitriol) may slightly increase intestinal absorption of magnesium (6). However, it is not clear whether magnesium absorption is calcitriol-dependent as is the absorption of calcium and phosphate. High calcium intake has not been found to affect magnesium balance in most studies. Inadequate blood magnesium levels are known to result in low blood calcium levels, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (2, 3).

Deficiency

Magnesium deficiency in healthy individuals who are consuming a balanced diet is quite rare because magnesium is abundant in both plant and animal foods and because the kidneys are able to limit urinary excretion of magnesium when intake is low. The following conditions increase the risk of magnesium deficiency (1):

  • Gastrointestinal disorders: Prolonged diarrhea, Crohn’s diseasemalabsorption syndromesceliac disease, surgical removal of a portion of the intestine, and intestinal inflammation due to radiation may all lead to magnesium depletion.
  • Renal disorders (magnesium wasting): Diabetes mellitus and long-term use of certain diuretics (see Drug interactions) may result in increased urinary loss of magnesium. Multiple other medications can also result in renal magnesium wasting (3).
  • Chronic alcoholism: Poor dietary intake, gastrointestinal problems, and increased urinary loss of magnesium may all contribute to magnesium depletion, which is frequently encountered in alcoholics.
  • Age: Several studies have found that elderly people have relatively low dietary intakes of magnesium (7, 8). Intestinal magnesium absorption tends to decrease with age and urinary magnesium excretion tends to increase with age; thus, suboptimal dietary magnesium intake may increase the risk of magnesium depletion in the elderly (2).

Although severe magnesium deficiency is uncommon, it has been induced experimentally. When magnesium deficiency was induced in humans, the earliest sign was decreased serum magnesium levels (hypomagnesemia). Over time, serum calcium levels also began to decrease (hypocalcemia) despite adequate dietary calcium. Hypocalcemia persisted despite increased secretion of parathyroid hormone (PTH), which regulates calcium homeostasis. Usually, increased PTH secretion quickly results in the mobilization of calcium from bone and normalization of blood calcium levels. As the magnesium depletion progressed, PTH secretion diminished to low levels. Along with hypomagnesemia, signs of severe magnesium deficiency included hypocalcemia, low serum potassium levels (hypokalemia), retention of sodium, low circulating levels of PTH, neurological and muscular symptoms (tremor, muscle spasms, tetany), loss of appetite, nausea, vomiting, and personality changes (3).

The Recommended Dietary Allowance (RDA)

In 1997, the Food and Nutrition Board of the Institute of Medicine increased the recommended dietary allowance (RDA) for magnesium, based on the results of recent, tightly controlled balance studies that utilized more accurate methods of measuring magnesium (2Table 1). Balance studies are useful for determining the amount of a nutrient that will prevent deficiency; however, such studies provide little information regarding the amount of a nutrient required for chronic disease prevention or optimum health.

Table 1. Recommended Dietary Allowance (RDA) for Magnesium
Life Stage Age Males (mg/day) Females (mg/day)
Infants 0-6 months 30 (AI) 30 (AI)
Infants 7-12 months 75 (AI) 75 (AI)
Children 1-3 years 80 80
Children 4-8 years 130 130
Children 9-13 years 240 240
Adolescents 14-18 years 410 360
Adults 19-30 years 400 310
Adults 31 years and older 420 320
Pregnancy 18 years and younger 400
Pregnancy 19-30 years 350
Pregnancy 31 years and older 360
Breast-feeding 18 years and younger 360
Breast-feeding 19-30 years 310
Breast-feeding 31 years and older 320

Disease Prevention

Metabolic syndrome

Low magnesium intakes have been associated with the diagnosis of metabolic syndrome. The concomitant presentation of several metabolic disorders in an individual, including dyslipidemia, hypertensioninsulin resistance, and obesity, increases the risk for type 2 diabetes mellitus and cardiovascular disease. Systemic inflammation, which contributes to the development of metabolic disorders, has been inversely correlated with magnesium intakes in a cross-sectional study of 11,686 middle-aged women; the lowest prevalence of metabolic syndrome was found in the group of women with the highest quintile of magnesium intakes (median intake, 422 mg/day) (9).

Hypertension (high blood pressure)

Large epidemiological study studies suggest a relationship between magnesium and blood pressure. However, the fact that foods high in magnesium (fruit, vegetables, whole grains) are frequently high in potassium and dietary fiber has made it difficult to evaluate the independent effects of magnesium on blood pressure. A prospective cohort study of more than 30,000 male health professionals found an inverse association between dietary fiber, potassium, and magnesium and the development of hypertension over a four-year period (10). In a similar study of more than 40,000 female registered nurses, dietary fiber and dietary magnesium were each inversely associated with systolic and diastolic blood pressures in those who did not develop hypertension over the four-year study period, but neither dietary fiber nor magnesium was related to the risk of developing hypertension (11). The Atherosclerosis Risk in Communities (ARIC) study examined dietary magnesium intake, magnesium blood levels, and risk of developing hypertension in 7,731 men and women over a six-year period (12). The risk of developing hypertension in both men and women decreased as serummagnesium levels increased, but the trend was statistically significant only in women.

However, circulating magnesium represents only 1% of total body stores and is tightly regulated; thus, serum magnesium levels might not best reflect magnesium status. A recent prospective study that followed 5,511 men and women for a median period of 7.6 years found that the highest levels of urinary magnesium excretion corresponded to a 25% reduction in risk of hypertension, but plasma magnesium levels were not correlated with risk of hypertension (13). In cohort of 28,349 women followed for 9.3 years, the risk of hypertension was 7% lower for those with the highest magnesium intakes (434 mg/day vs. 256 mg/day) (14). The relationship between magnesium intake and risk of hypertension suggests that magnesium supplementation might play a role in preventing hypertension; however, randomized controlled trials are needed to assess whether supplemental magnesium might help prevent hypertension in high-risk individuals.

Diabetes mellitus

Public health concerns regarding the epidemics of obesity and type 2 diabetes mellitus and the prominent role of magnesium in glucose metabolism have led scientists to investigate the relationship between magnesium intake and type 2 diabetes mellitus. A prospective study that followed more than 25,000 individuals, 35 to 65 years of age, for seven years found no difference in incidence of diabetes mellitus when comparing the highest (377 mg/day) quintile of magnesium intake to the lowest (268 mg/day) (15). However, inclusion of this study in a meta-analysis of eight cohort studies showed that risk of type 2 diabetes was inversely correlated with magnesium intake (15). A second meta-analysis found that an increase of 100 mg/day in magnesium intake was associated with a 15% decrease in the risk of developing type 2 diabetes (16). The most recent meta-analysis of 13 observational studies, published in the last 15 years and including almost 540,000 individuals and 24,500 new cases of diabetes, found higher magnesium intakes were associated with a lower risk of diabetes (17).

Insulin resistance, which is characterized by alterations in both insulin secretion by the pancreas and insulin action on target tissues, has been linked to magnesium deficiency. An inverse association between magnesium intakes and fasting insulin levels was evidenced in a meta-analysis of 11 cohort studies that followed more than 36,000 participants without diabetes (18). It is thought that pancreatic β-cells, which regulate insulin secretion and glucose tolerance, could become less responsive to changes in insulin sensitivity in magnesium-deficient subjects (19). A randomizeddouble-blindplacebo-controlled trial, which enrolled 97 individuals (without diabetes and with normal blood pressure) with significant hypomagnesemia (serum magnesium level ≤0.70 mmoles/L), showed that daily consumption of 638 mg of magnesium (from a solution of magnesium chloride) for three months improved the function of pancreatic β-cells, resulting in lower fasting glucose and insulin levels (20). Increased insulin sensitivity also accompanied the correction of magnesium deficiency in patients diagnosed with insulin resistance but not diabetes (21). Another study found that supplementation with 365 mg/day of magnesium (from magnesium aspartate hydrochloride) for six months reduced insulin resistance in 47 overweight individuals even though they displayed normal values of serum and intracellular magnesium (22). This suggests that magnesium might have additive effects on glucose tolerance and insulin sensitivity that go beyond the normalization of physiologic serum concentrations in deficient individuals.

Cardiovascular disease

A number of studies have found decreased mortality from cardiovascular disease in populations who routinely consume “hard” water. Hard (alkaline) water is generally high in magnesium but may also contain more calcium and fluoride than “soft” water, making the cardioprotective effects of hard water difficult to attribute to magnesium alone (23). One large prospective study (almost 14,000 men and women) found a significant trend for increasing serum magnesium levels to be associated with decreased risk of coronary heart disease (CHD) in women but not in men (24). However, the risk of CHD in the lowest quartile of dietary magnesium intake was not significantly higher than the risk in the highest quartile in men or women. This prospective study was included in a meta-analysis of 14 studies that found a 22% lower risk of CHD (but not fatal CHD) per 200 mg/day incremental intake in dietary magnesium (25). In another prospective study, which followed nearly 90,000 female nurses for 28 years, women in the highest quintile of magnesium intake had a 39% lower risk of fatal myocardial infarction (but not nonfatal myocardial infarction) compared to those in the lowest quintile (>342 mg/day versus <246 mg/day) (26). Higher magnesium intakes were associated with an 8%-11% reduction in stroke risk in two meta-analyses of prospective studies, each including over 240,000 participants (27, 28). Additionally, a meta-analysis of 13 prospective studies in over 475,000 participants reported that the risk of total cardiovascular events, including stroke, nonfatal myocardial infarction, and CHD, was 15% lower in individuals with higher intakes of magnesium (29). Finally, a meta-analysis of six prospective studies found no association between magnesium intake and cardiovascular mortality risk (30). However, a recent prospective study that followed 3,910 subjects for 10 years found significant correlations between hypomagnesemia and all-cause mortality, including cardiovascular-related mortality (31). Presently, well-controlled intervention trials are required to assess the benefit of magnesium supplementation in the prevention of cardiovascular disease.

Stroke

Occurrence of hypomagnesemia has been reported in patients who suffered from a subarachnoid hemorrhage caused by the rupture of a cerebral aneurysm (32). Poor neurologic outcomes following an aneurysmal subarachnoid hemorrhage (aSAH) have been linked to inappropriate calcium-dependent contraction of arteries (known as cerebral arterial vasospasm), leading to delayed cerebral ischemia (33). Magnesium sulfate is a calcium antagonist and potent vasodilator that has been considered in the prevention of vasospasm after aSAH. Several randomized controlled trials have assessed the effect of intravenous (IV) magnesium sulfate infusions. A meta-analysis of nine randomized controlled trials found that magnesium therapy after aSAH significantly reduced vasospasm but failed to prevent neurologic deterioration or decrease the risk of death (34). The most recent meta-analysis of 13 trials in 2,413 aSAH patients concluded that the infusion of magnesium sulfate had no benefits in terms of neurologic outcome and mortality, despite a reduction in the incidence of delayed cerebral ischemia (35). At present, the data advise against the use of intravenous magnesium in clinical practice for aSAH patients after normalization of their magnesium status.

Complications of heart surgery

Atrial arrhythmia is a condition defined as the occurrence of persistent heart rate abnormalities that often complicate the recovery of patients after cardiac surgery. The use of magnesium in the prophylaxis of postoperative atrial arrhythmia after coronary artery bypass grafting has been evaluated as a sole or adjunctive agent to classical antiarrhythmic molecules (namely, β-blockers and amiodarone) in several prospective, randomized controlled trials. A meta-analysis of 21 intervention studies showed that intravenous magnesium infusions could significantly reduce postoperative atrial arrhythmia in treated compared to untreated patients (36). However, a meta-analysis of five randomized controlled trials concerned with rhythm-control prophylaxis showed that intravenous magnesium added to β-blocker treatment did not decrease the risk of atrial arrhythmia compared to β-blocker alone and was associated with more adverse effects (bradycardia and hypotension) (37). Presently, the findings support the use of β-blockers and amiodarone, but not magnesium, in patients with contraindications to first-line antiarrhythmics.

Osteoporosis

Although decreased bone mineral density (BMD) is the primary feature of osteoporosis, other osteoporotic changes in the collagenous matrix and mineral components of bone may result in bones that are brittle and more susceptible to fracture. Magnesium comprises about 1% of bone mineral and is known to influence both bone matrix and bone mineral metabolism. As the magnesium content of bone mineral decreases, apatite crystals of bone become larger and more brittle. Some studies have found lower magnesium content and larger apatite crystals in bones of women with osteoporosis compared to women without the disease (38). Inadequate serum magnesium levels are known to result in low serum calcium levels, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (calcitriol), all of which can lead to increased bone loss (see the articles on Vitamin D and Calcium). A study of over 900 elderly men and women found that higher dietary magnesium intakes were associated with increased BMD at the hip in both men and women. However, because magnesium and potassium are present in many of the same foods, the effect of dietary magnesium could not be isolated (39). A cross-sectional study in over 2,000 elderly individuals reported that magnesium intake was positively associated with total-body BMD in white men and women but not in black men and women (40). More recently, a large cohort study conducted in almost two-thirds of the Norwegian population found the level of magnesium in drinking water was inversely correlated with risk of hip fracture (41).

Few studies have addressed the effect of magnesium supplementation on BMD or osteoporosis in humans. In a small group of postmenopausal women with osteoporosis, magnesium supplementation of 750 mg/day for the first six months followed by 250 mg/day for 18 more months resulted in increased BMD at the wrist after one year, with no further increase after two years of supplementation (42). A study in postmenopausal women who were taking estrogen replacement therapy and also a multivitamin found that supplementation with an additional 500 mg/day of magnesium and 600 mg/day of calcium resulted in increased BMD at the heel compared to postmenopausal women receiving only estrogen replacement therapy (43). Evidence is not yet sufficient to suggest that supplemental magnesium could be recommended in the prevention of osteoporosis unless normalization of serum magnesium levels is required. Moreover, it appears that high magnesium levels could be harmful to skeletal health by interfering with the action of the calciotropic hormones, PTH and calcitriol (44). Presently, the potential for increased magnesium intake to influence calcium and bone metabolism warrants more research with particular attention to its role in the prevention and treatment of osteoporosis.

Disease Treatment

The use of pharmacologic doses of magnesium to treat specific diseases is discussed below. Although many of the cited studies utilized supplemental magnesium at doses considerably higher than the tolerable upper intake level (UL), which is 350 mg/day set by the Food and Nutrition Board (see Safety), it is important to note that these studies were all conducted under medical supervision. Because of the potential risks of high doses of supplemental magnesium, especially in the presence of impaired kidney function, any disease treatment trial using magnesium doses higher than the UL should be conducted under medical supervision.

Pregnancy complications

Preeclampsia and eclampsia

Preeclampsia and eclampsia are pregnancy-specific conditions that may occur anytime after 20 weeks of pregnancy through six weeks following birth. Approximately 7% of pregnant women in the US develop preeclampsia-eclampsia. Preeclampsia (sometimes called toxemia of pregnancy) is defined as the presence of elevated blood pressure (hypertension), protein in the urine, and severe swelling (edema) during pregnancy. Eclampsia occurs with the addition of seizures to the triad of symptoms and is a significant cause of perinatal and maternal death (45). Although cases of preeclampsia are at high risk of developing eclampsia, one-quarter of eclamptic women do not initially exhibit preeclamptic symptoms (46). For many years, high-dose intravenous magnesium sulfate has been the treatment of choice for preventing eclamptic seizures that may occur in association with preeclampsia-eclampsia late in pregnancy or during labor (47, 48). A systematic review of seven randomized trials compared the administration of magnesium sulfate with diazepam (a known anticonvulsant) treatment on perinatal outcomes in 1,396 women with eclampsia. Risks of recurrent seizures and maternal death were significantly reduced by the magnesium regimen compared to diazepam. Moreover, the use of magnesium for the care of eclamptic women resulted in newborns with higher Apgar scores; there was no significant difference in the risk of preterm birth and perinatal mortality (46). Additional research has confirmed that infusion of magnesium sulfate should always be considered in the management of preeclampsia and eclampsia to prevent initial and recurrent seizures (49).

Perinatal neuroprotection

While intravenous magnesium sulfate is included in the medical care of preeclampsia and eclampsia, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support its use in two additional situations: specific conditions of short-term prolongation of pregnancy and neuroprotection of the fetus in anticipated premature delivery (50). The relationship between magnesium sulfate and risk of cerebral damage in premature infants has been assessed in observational studies. A meta-analysis of six case-control and five prospective cohort studies showed that the use of magnesium significantly reduced the risk of cerebral palsy, as well as mortality (51). However, the high degree of heterogeneity among the cohort studies and the fact that corticosteroid exposure (which is known to decrease antenatal mortality) was higher in the cases of children exposed to magnesium compared to controls imply a cautious interpretation of the results. However, a meta-analysis of five randomized controlled trials, which included a total of 6,145 babies, found that magnesium therapy given to mothers delivering before term decreased the risk of cerebral palsy and gross motor dysfunction, without modifying the risk of other neurologic impairments or mortality in early childhood (52). Another meta-analysis conducted on five randomized controlled trials found that intravenous magnesium administration to newborns who suffered from perinatal asphyxia could be beneficial in terms of short-term neurologic outcomes, although there was no effect on mortality (53). Nevertheless, additional trials are needed to evaluate the long-term benefits of magnesium in pediatric care.

Cardiovascular disease

Hypertension (high blood pressure)

While results from intervention studies have not been entirely consistent (2), the latest review of the data highlighted a therapeutic benefit of magnesium supplements in treating hypertension. A recent meta-analysis examined 22 randomizedplacebo-controlled trials of magnesium supplementation conducted in 1,173 individuals with either a normal blood pressure (normotensive) or hypertension, both treated or untreated with medications. Oral supplementation with magnesium (mean dose of 410 mg/day; range of 120 to 973 mg/day) for a median period of 11.3 months significantly reduced systolic blood pressure by 2-3 mm Hg and diastolic blood pressure by 3-4 mm Hg (54); a greater effect was seen at higher doses (≥370 mg/day). The results of 19 of the 22 trials included in the meta-analysis were previously reviewed together with another 25 intervention studies (55). The systematic examination of these 44 trials suggested a blood pressure-lowering effect associated with supplemental magnesium in hypertensive but not in normotensive individuals. Magnesium doses required to achieve a decrease in blood pressure appeared to depend on whether subjects with high blood pressure were treated with antihypertensive medications, including diuretics. Intervention trials on treated subjects showed a reduction in hypertension with magnesium doses from 243 mg/day to 486 mg/day, whereas untreated patients required doses above 486 mg/day to achieve a significant decrease in blood pressure. While oral magnesium supplementation may be helpful in hypertensive individuals who are depleted of magnesium due to chronic diuretic use and/or inadequate dietary intake (56), several dietary factors play a role in hypertension. For example, adherence to the DASH diet — a diet rich in fruit, vegetables, and low-fat dairy and low in saturated and total fats — has been linked to significant reductions in systolic and diastolic blood pressures (57). See the article in the Spring/Summer 2009 Research Newsletter, Dietary and Lifestyle Strategies to Control Blood Pressure.

Myocardial infarction (heart attack)

Results of a meta-analysis of randomizedplacebo-controlled trials indicated that an intravenous (IV) magnesium infusion given early after suspected myocardial infarction(MI) could decrease the risk of death. The most influential study included in the meta-analysis was a randomized, placebo-controlled trial in 2,316 patients that found a significant reduction in mortality (7.8% all-cause mortality in the experimental group vs. 10.3% all-cause mortality in the placebo group) in the group of patients given intravenous magnesium sulfate within 24 hours of suspected myocardial infarction (58). Follow-up from one to five years after treatment revealed that the mortality from cardiovascular disease was 21% lower in the magnesium treated group (59). However, a larger placebo-controlled trial that included more than 58,000 patients found no significant reduction in five-week mortality in patients treated with intravenous magnesium sulfate within 24 hours of suspected myocardial infarction, resulting in controversy regarding the efficacy of the treatment (60). A US survey of the treatment of more than 173,000 patients with acute MI found that only 5% were given IV magnesium in the first 24 hours after MI, and that mortality was higher in patients treated with IV magnesium compared to those not treated with magnesium (61). The most recent systematic review of 26 clinical trials, including 73,363 patients, concluded that IV magnesium likely does not reduce mortality following MI and thus should not be utilized as a treatment (62). Thus, the use of IV magnesium sulfate in the therapy of acute MI remains controversial.

Endothelial dysfunction

Vascular endothelial cells line arterial walls where they are in contact with the blood that flows through the circulatory system. Normally functioning vascular endothelium promotes vasodilation when needed, for example, during exercise, and inhibits the formation of blood clots. Conversely, endothelial dysfunction results in widespread vasoconstriction and coagulation abnormalities. In cardiovascular disease, chronic inflammation is associated with the formation of atherosclerotic plaques in arteries. Atherosclerosis impairs normal endothelial function, increasing the risk of vasoconstriction and clot formation, which may lead to heart attack or stroke (reviewed in 63). Research studies have indicated that pharmacologic doses of oral magnesium may improve endothelial function in individuals with cardiovascular disease. A randomizeddouble-blindplacebo-controlled trial in 50 men and women with stable coronary artery disease found that six months of oral magnesium supplementation (730 mg/day) resulted in a 12% improvement in flow-mediated vasodilation compared to placebo (64). In other words, the normal dilation response of the brachial (arm) artery to increased blood flow was improved. Magnesium supplementation also resulted in increased exercise tolerance during an exercise stress test compared to placebo. In another study of 42 patients with coronary artery disease who were already taking low-dose aspirin (an inhibitor of platelet aggregation), three months of oral magnesium supplementation (800 to 1,200 mg/day) resulted in an average 35% reduction in platelet-dependent thrombosis, a measure of the propensity of blood to clot (65). Additionally, a study in 657 women participating in the Nurses’ Health Study reported that dietary magnesium intake was inversely associated with E-selectin, a marker of endothelial dysfunction (66)In vitro studies using human endothelial cells have provided mechanistic insights into the association of low magnesium concentrations, chronic inflammation, and endothelial dysfunction (67). Finally, since magnesium can function as a calcium antagonist, it has been suggested that it could be utilized to slow down or reverse the calcification of vessels observed in patients with chronic kidney disease. The atherosclerotic process is often accelerated in these subjects, and patients with chronic kidney disease have higher rates of cardiovascular-related mortality compared to the general population (68). Additional studies are needed to assess whether magnesium may be of benefit in improving endothelial function in individuals at high risk for cardiovascular disease.

Diabetes mellitus

Magnesium depletion is commonly associated with both insulin-dependent (type 1) and non-insulin dependent (type 2) diabetes mellitus. Reduced serum levels of magnesium (hypomagnesemia) have been reported in 13.5% to 47.7% of individuals with type 2 diabetes (69). One cause of the depletion may be increased urinary loss of magnesium, which results from increased urinary excretion of glucose that accompanies poorly controlled diabetes. Magnesium depletion has been shown to increase insulin resistance in a few studies and may adversely affect blood glucose control in diabetes (70). One study reported that dietary magnesium supplements (390 mg/day of elemental magnesium for four weeks) improved glucose tolerance in elderly individuals (71). Another small study in nine patients with type 2 diabetes reported that supplemental magnesium (300 mg/day for 30 days), in the form of a liquid, magnesium-containing salt solution, improved fasting insulin levels but did not affect fasting glucose levels (72). Yet, the most recent meta-analysis of nine randomizeddouble-blind, controlled trials concluded that oral supplemental magnesium may lower fasting plasma glucose levels in individuals with diabetes (73). One randomized, double-blind, placebo-controlled study in 63 individuals with type 2 diabetes and hypomagnesemia found that those taking an oral magnesium chloride solution (638 mg/day of elemental magnesium) for 16 weeks had improved measures of insulin sensitivity and glycemic control compared to those taking a placebo (74). Large-scale, well-controlled studies are needed to determine whether magnesium supplementation has any long-term therapeutic benefit in patients with type 2 diabetes. However, correcting existing magnesium deficiencies may improve glucose metabolism and insulin sensitivity in those with diabetes.

Migraine headaches

Individuals who suffer from recurrent migraine headaches have lower intracellular magnesium levels (demonstrated in both red blood cells and white blood cells) than individuals who do not experience migraines (75). Additionally, the incidence of ionized magnesium deficiency has been found to be higher in women with menstrualmigraine compared to women who don’t experience migraines with menstruation (76). Oral magnesium supplementation has been shown to increase intracellular magnesium levels in individuals with migraines, leading to the hypothesis that magnesium supplementation might be helpful in decreasing the frequency and severity of migraine headaches. Two early placebo-controlled trials demonstrated modest decreases in the frequency of migraine headaches after supplementation with 600 mg/day of magnesium (75, 77). Another placebo-controlled trial in 86 children with frequent migraine headaches found that oral magnesium oxide (9 mg/kg body weight/day) reduced headache frequency over the 16-week intervention (78). However, there was no reduction in the frequency of migraine headaches with 485 mg/day of magnesium in another placebo-controlled study conducted in 69 adults suffering migraine attacks (79). The efficiency of magnesium absorption varies with the type of oral magnesium complex, and this might explain the conflicting results. Although no serious adverse effects were noted during these migraine headache trials, 19% to 40% of individuals taking the magnesium supplements have reported diarrhea and gastric (stomach) irritation.

The efficacy of magnesium infusions was also investigated in a randomized, single-blind, placebo-controlled, cross-over trial of 30 patients with migraine headaches (80). The administration of 1 gram of intravenous (IV) magnesium sulfate ended the attacks, abolished associated symptoms, and prevented recurrence within 24 hours in nearly 90% of the subjects. While this promising result was confirmed in another trial (81), two additional randomized, placebo-controlled studies found that magnesium sulfate was less effective than other molecules (e.g., metoclopramide) in treating migraines (82, 83). The most recent meta-analysis of five randomized, double-blind, controlled trials reported no beneficial effect of IV magnesium for migraine in adults (84). However, the effect of magnesium should be examined in larger studies targeting primarily migraine sufferers with hypomagnesemia (85).

Asthma

The occurrence of hypomagnesemia may be greater in patients with asthma than in individuals without asthma (86). Several clinical trials have examined the effect of intravenous (IV) magnesium infusions on acute asthmatic attacks. One double-blindplacebo-controlled trial in 38 adults with acute asthma, who did not respond to initial treatment in the emergency room, found improved lung function and decreased likelihood of hospitalization when IV magnesium sulfate was infused compared to a placebo (87). However, another placebo-controlled, double-blind study in 48 adults reported that IV infusion of magnesium sulfate did not improve lung function in patients experiencing an acute asthma attack (88). A systematic review of seven randomized controlled trials (five adult and two pediatric) concluded that IV magnesium sulfate is beneficial in patients with severe, acute asthma (89). In addition, a meta-analysis of five randomized placebo-controlled trials, involving 182 children with severe asthma, found that IV infusion of magnesium sulfate was associated with a 71% reduction in the need for hospitalization (90). In the most recent meta-analysis of 16 randomized controlled trials (11 adult and 5 pediatric), IV magnesium sulfate treatment was associated with a significant improvement of respiratory function in both adults and children with acute asthma treated with β2-agonists and systemic steroids (91). At present, available evidence indicates that IV magnesium infusion is an efficacious treatment for severe, acute asthma; however, oral magnesium supplementation is of no known value in the management of chronic asthma (92-94). Nebulized, inhaled magnesium for treating asthma requires further investigation. A meta-analysis of eight randomized controlled trials in asthmatic adults showed that nebulized, inhaled magnesium sulfate had benefits with respect to improved lung function and decreased hospital admissions (91). However, a recent systematic review of 16 randomized controlled trials, including adults, children, or both, found little evidence that inhaled magnesium sulfate, along with a β2-agonist, improved pulmonary function in patients with acute asthma (95).

Sources

Food sources

A large US national survey indicated that average magnesium intake is about 350 mg/day for men and about 260 mg/day for women — significantly below the current recommended dietary allowance (RDA). Magnesium intakes were even lower in men and women over 50 years of age (8). Such findings suggest that marginal magnesium deficiency may be relatively common in the US.

Since magnesium is part of chlorophyll, the green pigment in plants, green leafy vegetables are rich in magnesium. Unrefined grains (whole grains) and nuts also have high magnesium content. Meats and milk have an intermediate content of magnesium, while refined foods generally have the lowest. Water is a variable source of intake; harder water usually has a higher concentration of magnesium salts (2). Some foods that are relatively rich in magnesium are listed in Table 2, along with their magnesium content in milligrams (mg). For more information on the nutrient content of foods, search the USDA food composition database.

Table 2. Some Food Sources of Magnesium
Food Serving Magnesium (mg)
Cereal, all bran ½ cup 112
Cereal, oat bran ½ cup dry 96
Brown rice, medium-grain, cooked 1 cup 86
Fish, mackerel, cooked 3 ounces 82
Spinach, frozen, chopped, cooked ½ cup 78
Almonds 1 ounce (23 almonds) 77
Swiss chard, chopped, cooked ½ cup 75
Lima beans, large, immature seeds, cooked ½ cup 63
Cereal, shredded wheat 2 biscuits 61
Peanuts 1 ounce 48
Molasses, blackstrap 1 tablespoon 48
Hazelnuts 1 ounce (21 hazelnuts) 46
Okra, frozen, cooked ½ cup 37
Milk, 1% fat 8 fluid ounces 34
Banana 1 medium 32

Supplements

Magnesium supplements are available as magnesium oxide, magnesium gluconate, magnesium chloride, and magnesium citrate salts, as well as a number of amino acidchelates, including magnesium aspartate. Magnesium hydroxide is used as an ingredient in several antacids (96).

Safety

Toxicity

Adverse effects have not been identified from magnesium occurring naturally in food. However, adverse effects from excess magnesium have been observed with intakes of various magnesium salts (i.e., supplemental magnesium) (6). The initial symptom of excess magnesium supplementation is diarrhea — a well-known side effect of magnesium that is used therapeutically as a laxative. Individuals with impaired kidney function are at higher risk for adverse effects of magnesium supplementation, and symptoms of magnesium toxicity have occurred in people with impaired kidney function taking moderate doses of magnesium-containing laxatives or antacids. Elevated serum levels of magnesium (hypermagnesemia) may result in a fall in blood pressure (hypotension). Some of the later effects of magnesium toxicity, such as lethargy, confusion, disturbances in normal cardiac rhythm, and deterioration of kidney function, are related to severe hypotension. As hypermagnesemia progresses, muscle weakness and difficulty breathing may occur. Severe hypermagnesemia may result in cardiac arrest (2, 3). The Food and Nutrition Board (FNB) of the Institute of Medicine set the tolerable upper intake level (UL) for magnesium at 350 mg/day (Table 3); this UL represents the highest level of daily supplemental magnesium intake likely to pose no risk of diarrhea or gastrointestinal disturbance in almost all individuals. The FNB cautions that individuals with renal impairment are at higher risk for adverse effects from excess supplemental magnesium intake. However, the FNB also notes that there are some conditions that may warrant higher doses of magnesium under medical supervision (2).

Table 3. Tolerable Upper Intake Level (UL) for Supplemental Magnesium
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 65
Children 4-8 years 110
Children 9-13 years 350
Adolescents 14-18 years 350
Adults 19 years and older 350
*Source of intake should be from food and formula only.

Drug interactions

Magnesium interferes with the absorption of digoxin (a heart medication), nitrofurantoin (an antibiotic), and certain anti-malarial drugs, which could potentially reduce drug efficacy. Bisphosphonates (e.g., alendronate and etidronate), which are drugs used to treat osteoporosis, and magnesium should be taken two hours apart so that the absorption of the bisphosphonate is not inhibited. Magnesium has also been found to reduce the efficacy of chlorpromazine (a tranquilizer), penicillamine, oral anticoagulants, and the quinolone and tetracycline classes of antibiotics. Because intravenous magnesium has increased the effects of certain muscle-relaxing medications used during anesthesia, it is advisable to let medical staff know if you are taking oral magnesium supplements, laxatives, or antacids prior to surgical procedures. High doses of furosemide (Lasix) and some thiazide diuretics (e.g., hydrochlorothiazide), if taken for extended periods, may result in magnesium depletion (96, 97). Moreover, long-term use (three months or longer) of proton-pump inhibitors (drugs used to reduce the amount of stomach acid) may increase the risk of hypomagnesemia (98, 99). Many other medications may also result in renal magnesium loss (3).

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the latest RDA for magnesium intake (400-420 mg/day for men and 310-320 mg/day for women). Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement may ensure an intake of at least 100 mg of magnesium/day. Few multivitamin/mineral supplements contain more than 100 mg of magnesium due to its bulk. Because magnesium is plentiful in foods, eating a varied diet that provides green vegetables, whole grains, and nuts daily should provide the rest of an individual’s magnesium requirement.

Older adults (>50 years)

Older adults are less likely than younger adults to consume enough magnesium to meet their needs and should therefore take care to eat magnesium-rich foods in addition to taking a multivitamin/mineral supplement daily. Since older adults are more likely to have impaired kidney function, they should avoid taking more than 350 mg/day of supplemental magnesium without medical consultation (see Safety).

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Approximately one-third to one-half of patients with generalized Social Anxiety Disorder (SAD) do not experience adequate clinical benefit from current evidence-based treatment for SAD. This includes treatment with conventional approaches such as selective serotonin reuptake inhibitors (SSRIs) or venlafaxine and cognitive behavioral therapy (CBT). Failure of anxiety relief in patients with SAD is a source of substantial morbidity, distress, and decreases in quality of life.
Symptoms
Feelings of shyness or discomfort in certain situations aren’t necessarily signs of social anxiety disorder, particularly in children. Comfort levels in social situations vary, depending on the individual’s personality traits and life experiences. Some people are naturally reserved and others are more outgoing.
In contrast to everyday nervousness, social anxiety disorder includes fear, anxiety and avoidance that interferes with your daily routine, work, school or other activities.

Emotional and behavioral symptoms
Signs and symptoms of social anxiety disorder can include persistent:
• Fear of situations in which you may be judged
• Worrying about embarrassing or humiliating yourself
• Concern that you’ll offend someone
• Intense fear of interacting or talking with strangers
• Fear that others will notice that you look anxious
• Fear of physical symptoms that may cause you embarrassment, such as blushing, sweating, trembling or having a shaky voice
• Avoiding doing things or speaking to people out of fear of embarrassment
• Avoiding situations where you might be the center of attention
• Having anxiety in anticipation of a feared activity or event
• Spending time after a social situation analyzing your performance and identifying flaws in your interactions
• Expecting the worst possible consequences from a negative experience during a social situation
For children, anxiety about interacting with adults or peers may be shown by crying, having temper tantrums, clinging to parents or refusing to speak in social situations.
Performance type of social anxiety disorder is when you experience intense fear and anxiety only during speaking or performing in public, but not in other types of social situations.
Physical symptoms
Physical signs and symptoms can sometimes accompany social anxiety disorder and may include:
• Fast heartbeat
• Upset stomach or nausea
• Trouble catching your breath
• Dizziness or lightheadedness
• Confusion or feeling “out of body”
• Diarrhea
• Muscle tension
Avoiding normal social situations
Common, everyday experiences that may be hard to endure when you have social anxiety disorder include, for example:
• Using a public restroom
• Interacting with strangers
• Eating in front of others
• Making eye contact
• Initiating conversations
• Dating
• Attending parties or social gatherings
• Going to work or school
• Entering a room in which people are already seated
• Returning items to a store
Social anxiety disorder symptoms can change over time. They may flare up if you’re facing a lot of stress or demands. Although avoiding anxiety-producing situations may make you feel better in the short term, your anxiety is likely to persist over the long term if you don’t get treatment.
Ketamine
Converging lines of evidence from neuroimaging and pharmacological studies support the importance of glutamate abnormalities in the pathogenesis of SAD. In a previously conducted clinical study, an elevated glutamate to creatinine ratio was found in the anterior cingulate cortex of SAD patients when compared to healthy controls. Elevated brain glutamine levels have also been demonstrated in patients with SAD. Moreover, nonclinical rodent studies have established a strong link between glutamate regulation and anxiety.
Ketamine is a potent antagonist of the N-methyl-D-aspartate (NMDA) receptor, a major type of glutamate receptor in the brain. Ketamine is routinely used for anesthetic induction because of its dissociative properties. However in research studies and in some physician accounts of off-label clinical use, ketamine is an effective treatment for reducing symptoms of depressive and anxiety disorders. In multiple controlled clinical studies, ketamine has produced a rapid antidepressant effect in unipolar and bipolar depression. Ketamine’s anti-depressant effects peak 1-3 days following infusion and is observed long after ketamine has been metabolized and excreted by the body and after ketamine’s sedative and dissociative effects have dissipated.
The results of several clinical studies suggest that ketamine may also have significant anxiolytic effects. Patients with major depressive disorder given a single ketamine infusion have shown strong and significant reductions in comorbid anxiety symptoms. A trial including 11 depressed patients demonstrated a significant reduction in anxiety symptoms (Hamilton Anxiety Rating Scale (HAM-A)) following ketamine infusion. This improvement is supported by one of the earlier placebo-controlled trials of ketamine which demonstrated that the psychic anxiety item was one of 4 (out of 21) items on the Hamilton Depression Rating Scale (HAM-D) demonstrating significant improvement after ketamine infusion.

 

The National Institute of Mental Health Highlights Ketamine for Depression

 August 25, 2018

The National Institute of Mental Health (NIMH) issued a highlight on ketamine for treating depression.

The most commonly used antidepressants are largely variations on a theme; they increase the supply within synapses of a class of neurotransmitters believed to play a role in depression. While these drugs relieve depression for some, there is a weeks-long delay before they take effect, and some people with “treatment-resistant” depression do not respond at all.

The delay in effectiveness has suggested to scientists that the medication-induced changes in neurotransmitters are several steps away from processes more central to the root cause of depression. One possibility for a more proximal mechanism is glutamate, the primary excitatory, or activating, neurotransmitter in the brain. Preliminary studies suggested that inhibitors of glutamate could have antidepressant-like effects, and in a seminal clinical trial, the drug ketamine—which dampens glutamate signaling—lifted depression in as little as 2 hours in people with treatment-resistant depression.34

The discovery of rapidly acting antidepressants has transformed our expectations—we now look for treatments that will work in 6 hours rather than 6 weeks. But ketamine has some disadvantages; it has to be administered intravenously, the effects are transient, and it has side effects that require careful monitoring. However, results from clinical studies have confirmed the potential of the glutamate pathway as a target for the development of new antidepressants. Continuing research with ketamine has provided information on biomarkers that could be used to predict who will respond to treatment.35Clinical studies are also testing analogs of ketamine in an effort to develop glutamate inhibitors without ketamine’s side effects that can then be used in the clinic.36 Ketamine may also have potential for treating other mental illnesses; for example, a preliminary clinical trial reported that ketamine reduced the severity of symptoms in patients with PTSD. 37 Investigation of the role of glutamate signaling in other illnesses may provide the impetus to develop novel therapies based on this pathway.

Left: Change in the 21-item Hamilton Depression Rating Scale (HDRS) following ketamine or placebo treatment.
Right: Proportion of responders showing a 50 percent improvement on the HDRS following ketamine or placebo treatment.34

Source: Carlos Zarate, M.D., Experimental Therapeutics and Pathophysiology Branch, NIMH

One of the imperatives of clinical research going forward will be to demonstrate whether the ability of a compound to interact with a specific brain target is related to some measurable change in brain or behavioral activity that, in turn, can be associated with relief of symptoms. In a study of ketamine’s effects in patients in the depressive phase of bipolar disorder, ketamine restored pleasure-seeking behavior independent from and ahead of its other antidepressant effects. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom—loss of interest in pleasurable activities—which lasted up to 14 days.38 Brain scans traced the agent’s action to boosted activity in areas at the front and deep in the right hemisphere of the brain. This approach is consistent with the NIMH’s RDoC project, which calls for the study of functions—such as the ability to seek out and experience rewards—and their related brain systems that may identify subgroups of patients with common underlying dysfunctions that cut across traditional diagnostic categories.

The ketamine story shows that in some instances, a strong and repeatable clinical outcome stemming from a hypothesis about a specific molecular target (e.g., a glutamate receptor) can open up new arenas for basic research to explain the mechanisms of treatment response; basic studies can, in turn, provide data leading to improved treatments directed at that mechanism. A continuing focus on specific mechanisms will not only provide information on the potential of test compounds as depression medications, but will also help us understand which targets in the brain are worth aiming at in the quest for new therapies.

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22903 Charlottesville Charlottesville City
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22904 Charlottesville Charlottesville City
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22905 Charlottesville Charlottesville City
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22906 Charlottesville Charlottesville City
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22907 Charlottesville Charlottesville City
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22908 Charlottesville Charlottesville City
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22909 Charlottesville Albemarle
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22910 Charlottesville Charlottesville City
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22911 Charlottesville Albemarle
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22920 Afton Nelson
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22922 Arrington Nelson
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22923 Barboursville Orange
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22924 Batesville Albemarle
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22931 Covesville Albemarle
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22932 Crozet Albemarle
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22935 Dyke Greene
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22936 Earlysville Albemarle
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22937 Esmont Albemarle
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22938 Faber Nelson
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22939 Fishersville Augusta
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22940 Free Union Albemarle
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22942 Gordonsville Orange
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22943 Greenwood Albemarle
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22945 Ivy Albemarle
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22946 Keene Albemarle
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22947 Keswick Albemarle
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22948 Locust Dale Madison
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22949 Lovingston Nelson
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22952 Lyndhurst Augusta
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22957 Montpelier Station Orange
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22958 Nellysford Nelson
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22959 North Garden Albemarle
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22960 Orange Orange
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22963 Palmyra Fluvanna
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22964 Piney River Nelson
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22965 Quinque Greene
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22967 Roseland Nelson
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22968 Ruckersville Greene
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22969 Schuyler Nelson
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22971 Shipman Nelson
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22972 Somerset Orange
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22973 Stanardsville Greene
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22974 Troy Fluvanna
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22976 Tyro Nelson
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22980 Waynesboro Waynesboro City
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22987 White Hall Albemarle
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22989 Woodberry Forest Madison
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23001 Achilles Gloucester
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23002 Amelia Court House Amelia
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23003 Ark Gloucester
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23004 Arvonia Buckingham
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23005 Ashland Hanover
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23009 Aylett King William
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23011 Barhamsville New Kent
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23014 Beaumont Goochland
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23015 Beaverdam Hanover
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23018 Bena Gloucester
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23021 Bohannon Mathews
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23022 Bremo Bluff Fluvanna
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23023 Bruington King And Queen
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23024 Bumpass Louisa
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23025 Cardinal Mathews
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23027 Cartersville Cumberland
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23030 Charles City Charles City
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23031 Christchurch Middlesex
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23032 Church View Middlesex
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23035 Cobbs Creek Mathews
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23038 Columbia Goochland
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23039 Crozier Goochland
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23040 Cumberland Cumberland
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23043 Deltaville Middlesex
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23045 Diggs Mathews
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23047 Doswell Hanover
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23050 Dutton Gloucester
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23055 Fork Union Fluvanna
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23056 Foster Mathews
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23058 Glen Allen Henrico
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23059 Glen Allen Henrico
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23060 Glen Allen Henrico
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23061 Gloucester Gloucester
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23062 Gloucester Point Gloucester
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23063 Goochland Goochland
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23064 Grimstead Mathews
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23065 Gum Spring Goochland
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23066 Gwynn Mathews
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23067 Hadensville Goochland
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23068 Hallieford Mathews
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23069 Hanover Hanover
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23070 Hardyville Middlesex
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23071 Hartfield Middlesex
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23072 Hayes Gloucester
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23075 Highland Springs Henrico
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23076 Hudgins Mathews
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23079 Jamaica Middlesex
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23081 Jamestown James City
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23083 Jetersville Amelia
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23084 Kents Store Fluvanna
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23085 King And Queen Court House King And Queen
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23086 King William King William
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23089 Lanexa New Kent
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23090 Lightfoot York
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23091 Little Plymouth King And Queen
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23092 Locust Hill Middlesex
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23093 Louisa Louisa
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23101 Macon Powhatan
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23102 Maidens Goochland
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23103 Manakin Sabot Goochland
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23105 Mannboro Amelia
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23106 Manquin King William
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23107 Maryus Gloucester
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23108 Mascot King And Queen
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23109 Mathews Mathews
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23110 Mattaponi King And Queen
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23111 Mechanicsville Hanover
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23112 Midlothian Chesterfield
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23113 Midlothian Chesterfield
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23114 Midlothian Chesterfield
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23115 Millers Tavern Essex
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23116 Mechanicsville Hanover
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23117 Mineral Louisa
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23119 Moon Mathews
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23120 Moseley Chesterfield
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23123 New Canton Buckingham
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23124 New Kent New Kent
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23125 New Point Mathews
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23126 Newtown King And Queen
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23127 Norge James City
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23128 North Mathews
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23129 Oilville Goochland
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23130 Onemo Mathews
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23131 Ordinary Gloucester
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23138 Port Haywood Mathews
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23139 Powhatan Powhatan
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23140 Providence Forge New Kent
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23141 Quinton New Kent
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23146 Rockville Hanover
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23147 Ruthville Charles City
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23148 Saint Stephens Church King And Queen
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23149 Saluda Middlesex
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23150 Sandston Henrico
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23153 Sandy Hook Goochland
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23154 Schley Gloucester
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23155 Severn Gloucester
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23156 Shacklefords King And Queen
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23160 State Farm Goochland
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23161 Stevensville King And Queen
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23162 Studley Hanover
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23163 Susan Mathews
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23168 Toano James City
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23169 Topping Middlesex
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23170 Trevilians Louisa
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23173 University Of Richmond Richmond City
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23175 Urbanna Middlesex
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23176 Wake Middlesex
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23177 Walkerton King And Queen
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23178 Ware Neck Gloucester
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23180 Water View Middlesex
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23181 West Point King William
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23183 White Marsh Gloucester
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23184 Wicomico Gloucester
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23185 Williamsburg James City
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23186 Williamsburg Williamsburg City
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23187 Williamsburg Williamsburg City
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23188 Williamsburg James City
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23190 Woods Cross Roads Gloucester
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23192 Montpelier Hanover
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23218 Richmond Richmond City
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23219 Richmond Richmond City
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23220 Richmond Richmond City
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23221 Richmond Richmond City
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23222 Richmond Richmond City
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23223 Richmond Richmond City
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23224 Richmond Richmond City
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23225 Richmond Richmond City
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23226 Richmond Henrico
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23227 Richmond Henrico
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23228 Richmond Henrico
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23229 Richmond Henrico
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23230 Richmond Henrico
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23231 Richmond Henrico
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23232 Richmond Richmond City
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23233 Richmond Henrico
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23234 Richmond Chesterfield
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23235 Richmond Chesterfield
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23236 Richmond Chesterfield
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23237 Richmond Chesterfield
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23238 Richmond Henrico
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23240 Richmond Richmond City
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23241 Richmond Richmond City
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23242 Richmond Henrico
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23249 Richmond Richmond City
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23250 Richmond Henrico
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23255 Richmond Henrico
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23260 Richmond Richmond City
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23261 Richmond Richmond City
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23269 Richmond Richmond City
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23273 Richmond Richmond City
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23274 Richmond Richmond City
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23276 Richmond Richmond City
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23278 Richmond Richmond City
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23279 Richmond Richmond City
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23282 Richmond Richmond City
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23284 Richmond Richmond City
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23285 Richmond Richmond City
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23286 Richmond Richmond City
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23288 Richmond Henrico
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23289 Richmond Richmond City
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23290 Richmond Richmond City
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23291 Richmond Richmond City
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23292 Richmond Richmond City
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23293 Richmond Richmond City
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23294 Richmond Henrico
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23295 Richmond Richmond City
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23297 Richmond Chesterfield
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23298 Richmond Richmond City
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23301 Accomac Accomack
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23302 Assawoman Accomack
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23303 Atlantic Accomack
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23304 Battery Park Isle Of Wight
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23306 Belle Haven Accomack
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23307 Birdsnest Northampton
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23308 Bloxom Accomack
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23310 Cape Charles Northampton
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23313 Capeville Northampton
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23314 Carrollton Isle Of Wight
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23315 Carrsville Isle Of Wight
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23316 Cheriton Northampton
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23320 Chesapeake Chesapeake City
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23321 Chesapeake Chesapeake City
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23322 Chesapeake Chesapeake City
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23323 Chesapeake Chesapeake City
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23324 Chesapeake Chesapeake City
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23325 Chesapeake Chesapeake City
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23326 Chesapeake Chesapeake City
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23327 Chesapeake Chesapeake City
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23328 Chesapeake Chesapeake City
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23336 Chincoteague Island Accomack
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23337 Wallops Island Accomack
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23341 Craddockville Accomack
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23345 Davis Wharf Accomack
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23347 Eastville Northampton
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23350 Exmore Northampton
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23354 Franktown Northampton
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23356 Greenbackville Accomack
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23357 Greenbush Accomack
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23358 Hacksneck Accomack
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23359 Hallwood Accomack
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23389 Harborton Accomack
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23395 Horntown Accomack
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23396 Oak Hall Accomack
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23397 Isle Of Wight Isle Of Wight
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23398 Jamesville Northampton
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23399 Jenkins Bridge Accomack
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23401 Keller Accomack
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23404 Locustville Accomack
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23405 Machipongo Northampton
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23407 Mappsville Accomack
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23408 Marionville Northampton
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23409 Mears Accomack
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23410 Melfa Accomack
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23412 Modest Town Accomack
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23413 Nassawadox Northampton
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23414 Nelsonia Accomack
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23415 New Church Accomack
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23416 Oak Hall Accomack
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23417 Onancock Accomack
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23418 Onley Accomack
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23419 Oyster Northampton
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23420 Painter Accomack
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23421 Parksley Accomack
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23422 Pungoteague Accomack
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23423 Quinby Accomack
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23424 Rescue Isle Of Wight
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23426 Sanford Accomack
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23427 Saxis Accomack
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23429 Seaview Northampton
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23430 Smithfield Isle Of Wight
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23431 Smithfield Isle Of Wight
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23432 Suffolk Suffolk City
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23433 Suffolk Suffolk City
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23434 Suffolk Suffolk City
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23435 Suffolk Suffolk City
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23436 Suffolk Suffolk City
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23437 Suffolk Suffolk City
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23438 Suffolk Suffolk City
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23439 Suffolk Suffolk City
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23440 Tangier Accomack
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23441 Tasley Accomack
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23442 Temperanceville Accomack
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23443 Townsend Northampton
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23450 Virginia Beach Virginia Beach City
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23451 Virginia Beach Virginia Beach City
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23452 Virginia Beach Virginia Beach City
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23453 Virginia Beach Virginia Beach City
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23454 Virginia Beach Virginia Beach City
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23455 Virginia Beach Virginia Beach City
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23456 Virginia Beach Virginia Beach City
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23457 Virginia Beach Virginia Beach City
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23458 Virginia Beach Virginia Beach City
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23459 Virginia Beach Virginia Beach City
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23460 Virginia Beach Virginia Beach City
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23461 Virginia Beach Virginia Beach City
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23462 Virginia Beach Virginia Beach City
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23463 Virginia Beach Virginia Beach City
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23464 Virginia Beach Virginia Beach City
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23465 Virginia Beach Virginia Beach City
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23466 Virginia Beach Virginia Beach City
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23467 Virginia Beach Virginia Beach City
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23471 Virginia Beach Virginia Beach City
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23479 Virginia Beach Virginia Beach City
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23480 Wachapreague Accomack
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23482 Wardtown Northampton
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23483 Wattsville Accomack
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23486 Willis Wharf Northampton
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23487 Windsor Isle Of Wight
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23488 Withams Accomack
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23501 Norfolk Norfolk City
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23502 Norfolk Norfolk City
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23503 Norfolk Norfolk City
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23504 Norfolk Norfolk City
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23505 Norfolk Norfolk City
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23506 Norfolk Norfolk City
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23507 Norfolk Norfolk City
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23508 Norfolk Norfolk City
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23509 Norfolk Norfolk City
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23510 Norfolk Norfolk City
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23511 Norfolk Norfolk City
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23512 Norfolk Norfolk City
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23513 Norfolk Norfolk City
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23514 Norfolk Norfolk City
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23515 Norfolk Norfolk City
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23517 Norfolk Norfolk City
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23518 Norfolk Norfolk City
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23519 Norfolk Norfolk City
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23520 Norfolk Norfolk City
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23521 Norfolk Norfolk City
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23523 Norfolk Norfolk City
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23529 Norfolk Norfolk City
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23541 Norfolk Norfolk City
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23551 Norfolk Norfolk City
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23601 Newport News Newport News City
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23602 Newport News Newport News City
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23603 Newport News Newport News City
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23604 Fort Eustis Newport News City
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23605 Newport News Newport News City
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23606 Newport News Newport News City
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23607 Newport News Newport News City
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23608 Newport News Newport News City
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23609 Newport News Newport News City
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23612 Newport News Newport News City
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23628 Newport News Newport News City
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23630 Hampton Hampton City
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23651 Fort Monroe Hampton City
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23661 Hampton Hampton City
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23662 Poquoson Poquoson City
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23663 Hampton Hampton City
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23664 Hampton Hampton City
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23665 Hampton York
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23666 Hampton Hampton City
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23667 Hampton Hampton City
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23668 Hampton Hampton City
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23669 Hampton Hampton City
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23670 Hampton Hampton City
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23681 Hampton Hampton City
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23690 Yorktown York
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23691 Yorktown York
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23692 Yorktown York
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23693 Yorktown York
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23694 Lackey York
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23696 Seaford York
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23701 Portsmouth Portsmouth City
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23702 Portsmouth Portsmouth City
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23703 Portsmouth Portsmouth City
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23704 Portsmouth Portsmouth City
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23705 Portsmouth Portsmouth City
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23707 Portsmouth Portsmouth City
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23708 Portsmouth Portsmouth City
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23709 Portsmouth Portsmouth City
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23801 Fort Lee Prince George
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23803 Petersburg Petersburg City
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23804 Petersburg Petersburg City
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23805 Petersburg Petersburg City
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23806 Petersburg Petersburg City
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23821 Alberta Brunswick
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23822 Ammon Dinwiddie
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23824 Blackstone Nottoway
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23825 Blackstone Nottoway
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23827 Boykins Southampton
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23828 Branchville Southampton
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23829 Capron Southampton
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23830 Carson Dinwiddie
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23831 Chester Chesterfield
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23832 Chesterfield Chesterfield
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23833 Church Road Dinwiddie
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23834 Colonial Heights Colonial Heights City
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23836 Chester Chesterfield
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23837 Courtland Southampton
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23838 Chesterfield Chesterfield
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23839 Dendron Surry
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23840 Dewitt Dinwiddie
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23841 Dinwiddie Dinwiddie
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23842 Disputanta Prince George
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23843 Dolphin Brunswick
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23844 Drewryville Southampton
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23845 Ebony Brunswick
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23846 Elberon Surry
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23847 Emporia Greensville
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23850 Ford Dinwiddie
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23851 Franklin Franklin City
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23856 Freeman Brunswick
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23857 Gasburg Brunswick
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23860 Hopewell Hopewell City
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23866 Ivor Southampton
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23867 Jarratt Greensville
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23868 Lawrenceville Brunswick
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23870 Jarratt Greensville
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23872 Mc Kenney Dinwiddie
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23873 Meredithville Brunswick
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23874 Newsoms Southampton
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23875 Prince George Prince George
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23876 Rawlings Brunswick
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23878 Sedley Southampton
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23879 Skippers Greensville
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23881 Spring Grove Surry
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23882 Stony Creek Sussex
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23883 Surry Surry
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23884 Sussex Sussex
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23885 Sutherland Dinwiddie
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23887 Valentines Brunswick
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23888 Wakefield Sussex
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23889 Warfield Brunswick
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23890 Waverly Sussex
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23891 Waverly Sussex
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23893 White Plains Brunswick
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23894 Wilsons Dinwiddie
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23897 Yale Sussex
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23898 Zuni Isle Of Wight
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23899 Claremont Surry
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23901 Farmville Prince Edward
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23909 Farmville Prince Edward
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23915 Baskerville Mecklenburg
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23917 Boydton Mecklenburg
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23919 Bracey Mecklenburg
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23920 Brodnax Brunswick
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23921 Buckingham Buckingham
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23922 Burkeville Nottoway
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23923 Charlotte Court House Charlotte
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23924 Chase City Mecklenburg
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23927 Clarksville Mecklenburg
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23930 Crewe Nottoway
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23934 Cullen Charlotte
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23936 Dillwyn Buckingham
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23937 Drakes Branch Charlotte
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23938 Dundas Lunenburg
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23939 Evergreen Appomattox
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23941 Fort Mitchell Lunenburg
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23942 Green Bay Prince Edward
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23943 Hampden Sydney Prince Edward
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23944 Kenbridge Lunenburg
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23947 Keysville Charlotte
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23950 La Crosse Mecklenburg
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23952 Lunenburg Lunenburg
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23954 Meherrin Prince Edward
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23955 Nottoway Nottoway
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23958 Pamplin Appomattox
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23959 Phenix Charlotte
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23960 Prospect Prince Edward
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23962 Randolph Charlotte
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23963 Red House Charlotte
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23964 Red Oak Charlotte
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23966 Rice Prince Edward
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23967 Saxe Charlotte
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23968 Skipwith Mecklenburg
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23970 South Hill Mecklenburg
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23974 Victoria Lunenburg
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23976 Wylliesburg Charlotte
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24001 Roanoke Roanoke City
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24002 Roanoke Roanoke City
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24003 Roanoke Roanoke City
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24004 Roanoke Roanoke City
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24005 Roanoke Roanoke City
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24006 Roanoke Roanoke City
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24007 Roanoke Roanoke City
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24008 Roanoke Roanoke City
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24009 Roanoke Roanoke City
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24010 Roanoke Roanoke City
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24011 Roanoke Roanoke City
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24012 Roanoke Roanoke City
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24013 Roanoke Roanoke City
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24014 Roanoke Roanoke City
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24015 Roanoke Roanoke City
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24016 Roanoke Roanoke City
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24017 Roanoke Roanoke City
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24018 Roanoke Roanoke
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24019 Roanoke Roanoke
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24020 Roanoke Roanoke
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24022 Roanoke Roanoke City
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24023 Roanoke Roanoke City
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24024 Roanoke Roanoke City
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24025 Roanoke Roanoke City
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24026 Roanoke Roanoke City
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24027 Roanoke Roanoke City
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24028 Roanoke Roanoke City
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24029 Roanoke Roanoke City
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24030 Roanoke Roanoke City
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24031 Roanoke Roanoke City
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24032 Roanoke Roanoke City
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24033 Roanoke Roanoke City
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24034 Roanoke Roanoke City
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24035 Roanoke Roanoke City
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24036 Roanoke Roanoke City
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24037 Roanoke Roanoke City
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24038 Roanoke Roanoke City
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24040 Roanoke Roanoke City
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24042 Roanoke Roanoke City
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24043 Roanoke Roanoke City
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24044 Roanoke Roanoke City
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24045 Roanoke Roanoke City
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24048 Roanoke Roanoke City
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24050 Roanoke Botetourt
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24053 Ararat Patrick
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24054 Axton Henry
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24055 Bassett Henry
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24058 Belspring Pulaski
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24059 Bent Mountain Roanoke
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24060 Blacksburg Montgomery
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24061 Blacksburg Montgomery
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24062 Blacksburg Montgomery
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24063 Blacksburg Montgomery
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24064 Blue Ridge Botetourt
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24065 Boones Mill Franklin
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24066 Buchanan Botetourt
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24067 Callaway Franklin
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24068 Christiansburg Montgomery
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24069 Cascade Pittsylvania
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24070 Catawba Roanoke
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24072 Check Floyd
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24073 Christiansburg Montgomery
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24076 Claudville Patrick
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24077 Cloverdale Botetourt
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24078 Collinsville Henry
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24079 Copper Hill Floyd
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24082 Critz Patrick
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24083 Daleville Botetourt
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24084 Dublin Pulaski
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24085 Eagle Rock Botetourt
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24086 Eggleston Giles
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24087 Elliston Montgomery
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24088 Ferrum Franklin
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24089 Fieldale Henry
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24090 Fincastle Botetourt
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24091 Floyd Floyd
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24092 Glade Hill Franklin
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24093 Glen Lyn Giles
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24095 Goodview Bedford
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24101 Hardy Franklin
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24102 Henry Franklin
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24104 Huddleston Bedford
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24105 Indian Valley Floyd
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24111 Mc Coy Montgomery
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24112 Martinsville Martinsville City
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24113 Martinsville Martinsville City
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24114 Martinsville Martinsville City
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24115 Martinsville Martinsville City
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24120 Meadows Of Dan Patrick
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24121 Moneta Bedford
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24122 Montvale Bedford
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24124 Narrows Giles
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24126 Newbern Pulaski
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24127 New Castle Craig
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24128 Newport Giles
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24129 New River Pulaski
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24130 Oriskany Botetourt
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24131 Paint Bank Craig
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24132 Parrott Pulaski
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24133 Patrick Springs Patrick
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24134 Pearisburg Giles
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24136 Pembroke Giles
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24137 Penhook Franklin
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24138 Pilot Montgomery
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24139 Pittsville Pittsylvania
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24141 Radford Radford
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24142 Radford Radford
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24143 Radford Radford
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24146 Redwood Franklin
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24147 Rich Creek Giles
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24148 Ridgeway Henry
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24149 Riner Montgomery
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24150 Ripplemead Giles
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24151 Rocky Mount Franklin
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24153 Salem Salem
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24155 Roanoke Salem
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24157 Roanoke Salem
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24161 Sandy Level Pittsylvania
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24162 Shawsville Montgomery
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24165 Spencer Henry
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24167 Staffordsville Giles
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24168 Stanleytown Henry
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24171 Stuart Patrick
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24174 Thaxton Bedford
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24175 Troutville Botetourt
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24176 Union Hall Franklin
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24177 Vesta Patrick
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24178 Villamont Bedford
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24179 Vinton Roanoke
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24184 Wirtz Franklin
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24185 Woolwine Patrick
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24201 Bristol Bristol
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24202 Bristol Washington
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24203 Bristol Bristol
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24209 Bristol Bristol
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24210 Abingdon Washington
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24211 Abingdon Washington
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24212 Abingdon Washington
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24215 Andover Wise
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24216 Appalachia Wise
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24217 Bee Dickenson
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24218 Ben Hur Lee
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24219 Big Stone Gap Wise
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24220 Birchleaf Dickenson
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24221 Blackwater Lee
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24224 Castlewood Russell
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24225 Cleveland Russell
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24226 Clinchco Dickenson
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24228 Clintwood Dickenson
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24230 Coeburn Wise
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24236 Damascus Washington
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24237 Dante Russell
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24239 Davenport Buchanan
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24243 Dryden Lee
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24244 Duffield Scott
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24245 Dungannon Scott
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24246 East Stone Gap Wise
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24248 Ewing Lee
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24250 Fort Blackmore Scott
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24251 Gate City Scott
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24256 Haysi Dickenson
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24258 Hiltons Scott
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24260 Honaker Russell
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24263 Jonesville Lee
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24265 Keokee Lee
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24266 Lebanon Russell
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24269 Mc Clure Dickenson
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24270 Mendota Washington
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24271 Nickelsville Scott
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24272 Nora Dickenson
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24273 Norton Norton City
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24277 Pennington Gap Lee
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24279 Pound Wise
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24280 Rosedale Russell
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24281 Rose Hill Lee
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24282 Saint Charles Lee
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24283 Saint Paul Wise
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24290 Weber City Scott
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24292 Whitetop Grayson
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24293 Wise Wise
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24301 Pulaski Pulaski
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24311 Atkins Smyth
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24312 Austinville Wythe
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24313 Barren Springs Wythe
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24314 Bastian Bland
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24315 Bland Bland
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24316 Broadford Tazewell
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24317 Cana Carroll
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24318 Ceres Bland
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24319 Chilhowie Smyth
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24322 Cripple Creek Wythe
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24323 Crockett Wythe
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24324 Draper Pulaski
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24325 Dugspur Carroll
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24326 Elk Creek Grayson
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24327 Emory Washington
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24328 Fancy Gap Carroll
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24330 Fries Grayson
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24333 Galax Galax City
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24340 Glade Spring Washington
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24343 Hillsville Carroll
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24347 Hiwassee Pulaski
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24348 Independence Grayson
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24350 Ivanhoe Wythe
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24351 Lambsburg Carroll
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24352 Laurel Fork Carroll
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24354 Marion Smyth
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24360 Max Meadows Wythe
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24361 Meadowview Washington
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24363 Mouth Of Wilson Grayson
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24366 Rocky Gap Bland
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24368 Rural Retreat Wythe
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24370 Saltville Smyth
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24374 Speedwell Wythe
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24375 Sugar Grove Smyth
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24377 Tannersville Tazewell
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24378 Troutdale Grayson
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24380 Willis Floyd
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24381 Woodlawn Carroll
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24382 Wytheville Wythe
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24401 Staunton Staunton City
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24402 Staunton Staunton City
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24411 Augusta Springs Augusta
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24412 Bacova Bath
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24413 Blue Grass Highland
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24415 Brownsburg Rockbridge
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24416 Buena Vista Buena Vista City
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24421 Churchville Augusta
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24422 Clifton Forge Alleghany
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24426 Covington Covington City
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24430 Craigsville Augusta
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24431 Crimora Augusta
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24432 Deerfield Augusta
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24433 Doe Hill Highland
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24435 Fairfield Rockbridge
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24437 Fort Defiance Augusta
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24438 Glen Wilton Botetourt
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24439 Goshen Rockbridge
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24440 Greenville Augusta
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24441 Grottoes Rockingham
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24442 Head Waters Highland
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24445 Hot Springs Bath
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24448 Iron Gate Alleghany
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24450 Lexington Lexington City
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24457 Low Moor Alleghany
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24458 Mc Dowell Highland
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24459 Middlebrook Augusta
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24460 Millboro Bath
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24463 Mint Spring Augusta
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24464 Montebello Nelson
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24465 Monterey Highland
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24467 Mount Sidney Augusta
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24468 Mustoe Highland
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24469 New Hope Augusta
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24471 Port Republic Rockingham
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24472 Raphine Rockbridge
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24473 Rockbridge Baths Rockbridge
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24474 Selma Alleghany
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24476 Steeles Tavern Augusta
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24477 Stuarts Draft Augusta
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24479 Swoope Augusta
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24482 Verona Augusta
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24483 Vesuvius Rockbridge
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24484 Warm Springs Bath
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24485 West Augusta Augusta
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24486 Weyers Cave Augusta
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24487 Williamsville Bath
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24501 Lynchburg Lynchburg City
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24502 Lynchburg Lynchburg City
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24503 Lynchburg Lynchburg City
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24504 Lynchburg Lynchburg City
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24505 Lynchburg Lynchburg City
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24506 Lynchburg Lynchburg City
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24512 Lynchburg Lynchburg City
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24513 Lynchburg Lynchburg City
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24514 Lynchburg Lynchburg City
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24515 Lynchburg Lynchburg City
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24517 Altavista Campbell
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24520 Alton Halifax
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24521 Amherst Amherst
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24522 Appomattox Appomattox
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24523 Bedford Bedford
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24526 Big Island Bedford
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24527 Blairs Pittsylvania
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24528 Brookneal Campbell
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24529 Buffalo Junction Mecklenburg
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24530 Callands Pittsylvania
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24531 Chatham Pittsylvania
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24533 Clifford Amherst
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24534 Clover Halifax
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24535 Cluster Springs Halifax
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24536 Coleman Falls Bedford
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24538 Concord Campbell
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24539 Crystal Hill Halifax
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24540 Danville Danville City
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24541 Danville Danville City
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24543 Danville Danville City
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24544 Danville Danville City
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24549 Dry Fork Pittsylvania
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24550 Evington Campbell
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24551 Forest Bedford
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24553 Gladstone Nelson
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24554 Gladys Campbell
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24555 Glasgow Rockbridge
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24556 Goode Bedford
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24557 Gretna Pittsylvania
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24558 Halifax Halifax
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24562 Howardsville Buckingham
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24563 Hurt Pittsylvania
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24565 Java Pittsylvania
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24566 Keeling Pittsylvania
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24569 Long Island Pittsylvania
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24570 Lowry Bedford
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24571 Lynch Station Campbell
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24572 Madison Heights Amherst
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24574 Monroe Amherst
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24576 Naruna Campbell
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24577 Nathalie Halifax
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24578 Natural Bridge Rockbridge
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24579 Natural Bridge Station Rockbridge
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24580 Nelson Mecklenburg
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24581 Norwood Nelson
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24586 Ringgold Pittsylvania
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24588 Rustburg Campbell
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24589 Scottsburg Halifax
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24590 Scottsville Albemarle
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24592 South Boston Halifax
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24593 Spout Spring Appomattox
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24594 Sutherlin Pittsylvania
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24595 Sweet Briar Amherst
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24597 Vernon Hill Halifax
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24598 Virgilina Halifax
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24599 Wingina Buckingham
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24601 Amonate Tazewell
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24602 Bandy Tazewell
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24603 Big Rock Buchanan
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24604 Bishop Tazewell
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24605 Bluefield Tazewell
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24606 Boissevain Tazewell
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24607 Breaks Dickenson
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24608 Burkes Garden Tazewell
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24609 Cedar Bluff Tazewell
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24612 Doran Tazewell
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24613 Falls Mills Tazewell
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24614 Grundy Buchanan
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24619 Horsepen Tazewell
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24620 Hurley Buchanan
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24622 Jewell Ridge Tazewell
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24624 Keen Mountain Buchanan
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24627 Mavisdale Buchanan
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24628 Maxie Buchanan
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24630 North Tazewell Tazewell
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24631 Oakwood Buchanan
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24634 Pilgrims Knob Buchanan
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24635 Pocahontas Tazewell
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24637 Pounding Mill Tazewell
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24639 Raven Buchanan
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24640 Red Ash Tazewell
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24641 Richlands Tazewell
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24646 Rowe Buchanan
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24647 Shortt Gap Buchanan
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24649 Swords Creek Russell
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24651 Tazewell Tazewell
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24656 Vansant Buchanan
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24657 Whitewood Buchanan
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24658 Wolford Buchanan
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24701 Bluefield Mercer
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24712 Athens Mercer
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24714 Beeson Mercer
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24715 Bramwell Mercer
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24716 Bud Wyoming
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24719 Covel Wyoming
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24724 Freeman Mercer
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24726 Herndon Wyoming
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24729 Hiawatha Mercer
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24731 Kegley Mercer
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24732 Kellysville Mercer
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24733 Lashmeet Mercer
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24736 Matoaka Mercer
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24737 Montcalm Mercer
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24738 Nemours Mercer
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24739 Oakvale Mercer
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24740 Princeton Mercer
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24747 Rock Mercer
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24751 Wolfe Mercer
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24801 Welch Mcdowell
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24808 Anawalt Mcdowell
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24811 Avondale Mcdowell
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24813 Bartley Mcdowell
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24815 Berwind Mcdowell
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24816 Big Sandy Mcdowell
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24817 Bradshaw Mcdowell
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24818 Brenton Wyoming
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24822 Clear Fork Wyoming
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24823 Coal Mountain Wyoming
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24824 Coalwood Mcdowell
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24826 Cucumber Mcdowell
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24827 Cyclone Wyoming
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24828 Davy Mcdowell
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24829 Eckman Mcdowell
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24830 Elbert Mcdowell
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24831 Elkhorn Mcdowell
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24834 Fanrock Wyoming
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24836 Gary Mcdowell
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24839 Hanover Wyoming
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24842 Hemphill Mcdowell
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24843 Hensley Mcdowell
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24844 Iaeger Mcdowell
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24845 Ikes Fork Wyoming
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24846 Isaban Mcdowell
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24847 Itmann Wyoming
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24848 Jenkinjones Mcdowell
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24849 Jesse Wyoming
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24850 Jolo Mcdowell
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24851 Justice Mingo
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24853 Kimball Mcdowell
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24854 Kopperston Wyoming
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24855 Kyle Mcdowell
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24857 Lynco Wyoming
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24859 Marianna Wyoming
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24860 Matheny Wyoming
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24861 Maybeury Mcdowell
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24862 Mohawk Mcdowell
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24866 Newhall Mcdowell
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24867 New Richmond Wyoming
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24868 Northfork Mcdowell
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24869 North Spring Wyoming
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24870 Oceana Wyoming
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24871 Pageton Mcdowell
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24872 Panther Mcdowell
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24873 Paynesville Mcdowell
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24874 Pineville Wyoming
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24878 Premier Mcdowell
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24879 Raysal Mcdowell
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24880 Rock View Wyoming
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24881 Roderfield Mcdowell
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24882 Simon Wyoming
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24884 Squire Mcdowell
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24887 Switchback Mcdowell
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24888 Thorpe Mcdowell
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24892 War Mcdowell
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24894 Warriormine Mcdowell
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24895 Wilcoe Mcdowell
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24898 Wyoming Wyoming
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24901 Lewisburg Greenbrier
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24902 Fairlea Greenbrier
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24910 Alderson Greenbrier
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24915 Arbovale Pocahontas
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24916 Asbury Greenbrier
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24918 Ballard Monroe
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24920 Bartow Pocahontas
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24924 Buckeye Pocahontas
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24925 Caldwell Greenbrier
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24927 Cass Pocahontas
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24931 Crawley Greenbrier
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24934 Dunmore Pocahontas
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24935 Forest Hill Summers
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24938 Frankford Greenbrier
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24941 Gap Mills Monroe
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24943 Grassy Meadows Greenbrier
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24944 Green Bank Pocahontas
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24945 Greenville Monroe
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24946 Hillsboro Pocahontas
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24951 Lindside Monroe
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24954 Marlinton Pocahontas
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24957 Maxwelton Greenbrier
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24961 Neola Greenbrier
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24962 Pence Springs Summers
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24963 Peterstown Monroe
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24966 Renick Greenbrier
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24970 Ronceverte Greenbrier
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24974 Secondcreek Monroe
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24976 Sinks Grove Monroe
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24977 Smoot Greenbrier
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24981 Talcott Summers
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24983 Union Monroe
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24984 Waiteville Monroe
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24985 Wayside Monroe
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24986 White Sulphur Springs Greenbrier
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24991 Williamsburg Greenbrier
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24993 Wolfcreek Monroe
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25002 Alloy Fayette
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25003 Alum Creek Kanawha
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25005 Amma Roane
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25007 Arnett Raleigh
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25008 Artie Raleigh
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25009 Ashford Boone
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25011 Bancroft Putnam
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25015 Belle Kanawha
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25019 Bickmore Clay
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25021 Bim Boone
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25022 Blair Logan
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25024 Bloomingrose Boone
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25025 Blount Kanawha
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25026 Blue Creek Kanawha
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25028 Bob White Boone
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25030 Bomont Clay
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25031 Boomer Fayette
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25033 Buffalo Putnam
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25035 Cabin Creek Kanawha
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25036 Cannelton Fayette
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25039 Cedar Grove Kanawha
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25040 Charlton Heights Fayette
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25043 Clay Clay
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25044 Clear Creek Raleigh
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25045 Clendenin Kanawha
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25047 Clothier Logan
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25048 Colcord Raleigh
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25049 Comfort Boone
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25051 Costa Boone
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25053 Danville Boone
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25054 Dawes Kanawha
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25057 Deep Water Fayette
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25059 Dixie Nicholas
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25060 Dorothy Raleigh
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25061 Drybranch Kanawha
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25062 Dry Creek Raleigh
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25063 Duck Clay
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25064 Dunbar Kanawha
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25067 East Bank Kanawha
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25070 Eleanor Putnam
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25071 Elkview Kanawha
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25075 Eskdale Kanawha
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25076 Ethel Logan
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25079 Falling Rock Kanawha
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25081 Foster Boone
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25082 Fraziers Bottom Putnam
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25083 Gallagher Kanawha
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25085 Gauley Bridge Fayette
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25086 Glasgow Kanawha
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25088 Glen Clay
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25090 Glen Ferris Fayette
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25093 Gordon Boone
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25102 Handley Kanawha
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25103 Hansford Kanawha
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25106 Henderson Mason
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25107 Hernshaw Kanawha
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25108 Hewett Boone
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25109 Hometown Putnam
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25110 Hugheston Kanawha
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25111 Indore Clay
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25112 Institute Kanawha
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25113 Ivydale Clay
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25114 Jeffrey Boone
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25115 Kanawha Falls Fayette
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25118 Kimberly Fayette
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25119 Kincaid Fayette
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25121 Lake Logan
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25123 Leon Mason
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25124 Liberty Putnam
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25125 Lizemores Clay
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25126 London Kanawha
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25130 Madison Boone
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25132 Mammoth Kanawha
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25133 Maysel Clay
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25134 Miami Kanawha
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25136 Montgomery Fayette
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25139 Mount Carbon Fayette
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25140 Naoma Raleigh
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25141 Nebo Clay
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25142 Nellis Boone
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25143 Nitro Kanawha
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25148 Orgas Boone
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25149 Ottawa Boone
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25152 Page Fayette
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25154 Peytona Boone
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25156 Pinch Kanawha
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25159 Poca Putnam
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25160 Pond Gap Kanawha
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25161 Powellton Fayette
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25162 Pratt Kanawha
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25164 Procious Clay
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25165 Racine Boone
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25168 Red House Putnam
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25169 Ridgeview Boone
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25173 Robson Fayette
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25174 Rock Creek Raleigh
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25177 Saint Albans Kanawha
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25180 Saxon Boone
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25181 Seth Boone
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25183 Sharples Logan
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25185 Mount Olive Fayette
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25186 Smithers Fayette
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25187 Southside Mason
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25193 Sylvester Boone
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25201 Tad Kanawha
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25202 Tornado Kanawha
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25203 Turtle Creek Boone
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25204 Twilight Boone
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25205 Uneeda Boone
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25206 Van Boone
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25208 Wharton Boone
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25209 Whitesville Boone
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25211 Widen Clay
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25213 Winfield Putnam
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25214 Winifrede Kanawha
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25231 Advent Jackson
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25234 Arnoldsburg Calhoun
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25235 Chloe Calhoun
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25239 Cottageville Jackson
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25241 Evans Jackson
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25243 Gandeeville Roane
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25244 Gay Jackson
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25245 Given Jackson
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25247 Hartford Mason
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25248 Kenna Jackson
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25251 Left Hand Roane
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25252 Le Roy Jackson
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25253 Letart Mason
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25259 Looneyville Roane
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25260 Mason Mason
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25261 Millstone Calhoun
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25262 Millwood Jackson
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25264 Mount Alto Mason
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25265 New Haven Mason
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25266 Newton Roane
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25267 Normantown Gilmer
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25268 Orma Calhoun
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25270 Reedy Roane
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25271 Ripley Jackson
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25275 Sandyville Jackson
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25276 Spencer Roane
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25285 Wallback Clay
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25286 Walton Roane
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25287 West Columbia Mason
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25301 Charleston Kanawha
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25302 Charleston Kanawha
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25303 Charleston Kanawha
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25304 Charleston Kanawha
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25305 Charleston Kanawha
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25306 Charleston Kanawha
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25309 Charleston Kanawha
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25311 Charleston Kanawha
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25312 Charleston Kanawha
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25313 Charleston Kanawha
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25314 Charleston Kanawha
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25315 Charleston Kanawha
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25317 Charleston Kanawha
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25320 Charleston Kanawha
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25321 Charleston Kanawha
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25322 Charleston Kanawha
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25323 Charleston Kanawha
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25324 Charleston Kanawha
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25325 Charleston Kanawha
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25326 Charleston Kanawha
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25327 Charleston Kanawha
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25328 Charleston Kanawha
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25329 Charleston Kanawha
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25330 Charleston Kanawha
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25331 Charleston Kanawha
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25332 Charleston Kanawha
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25333 Charleston Kanawha
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25334 Charleston Kanawha
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25335 Charleston Kanawha
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25336 Charleston Kanawha
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25337 Charleston Kanawha
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25338 Charleston Kanawha
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25339 Charleston Kanawha
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25350 Charleston Kanawha
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25356 Charleston Kanawha
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25357 Charleston Kanawha
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25358 Charleston Kanawha
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25360 Charleston Kanawha
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25361 Charleston Kanawha
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25362 Charleston Kanawha
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25364 Charleston Kanawha
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25365 Charleston Kanawha
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25375 Charleston Kanawha
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25387 Charleston Kanawha
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25389 Charleston Kanawha
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25392 Charleston Kanawha
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25396 Charleston Kanawha
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25401 Martinsburg Berkeley
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25402 Martinsburg Berkeley
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25403 Martinsburg Berkeley
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25404 Martinsburg Berkeley
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25405 Martinsburg Berkeley
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25410 Bakerton Jefferson
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25411 Berkeley Springs Morgan
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25413 Bunker Hill Berkeley
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25414 Charles Town Jefferson
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25419 Falling Waters Berkeley
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25420 Gerrardstown Berkeley
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25421 Glengary Berkeley
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25422 Great Cacapon Morgan
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25423 Halltown Jefferson
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25425 Harpers Ferry Jefferson
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25427 Hedgesville Berkeley
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25428 Inwood Berkeley
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25429 Martinsburg Berkeley
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25430 Kearneysville Jefferson
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25431 Levels Hampshire
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25432 Millville Jefferson
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25434 Paw Paw Morgan
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25437 Points Hampshire
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25438 Ranson Jefferson
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25440 Ridgeway Berkeley
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25441 Rippon Jefferson
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25442 Shenandoah Junction Jefferson
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25443 Shepherdstown Jefferson
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25444 Slanesville Hampshire
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25446 Summit Point Jefferson
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25501 Alkol Lincoln
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25502 Apple Grove Mason
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25503 Ashton Mason
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25504 Barboursville Cabell
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25505 Big Creek Logan
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25506 Branchland Lincoln
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25507 Ceredo Wayne
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25508 Chapmanville Logan
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25510 Culloden Cabell
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25511 Dunlow Wayne
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25512 East Lynn Wayne
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25514 Fort Gay Wayne
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25515 Gallipolis Ferry Mason
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25517 Genoa Wayne
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25520 Glenwood Mason
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25521 Griffithsville Lincoln
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25523 Hamlin Lincoln
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25524 Harts Lincoln
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25526 Hurricane Putnam
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25529 Julian Boone
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25530 Kenova Wayne
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25534 Kiahsville Wayne
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25535 Lavalette Wayne
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25537 Lesage Cabell
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25540 Midkiff Lincoln
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25541 Milton Cabell
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25544 Myra Lincoln
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25545 Ona Cabell
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25547 Pecks Mill Logan
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25550 Point Pleasant Mason
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25555 Prichard Wayne
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25557 Ranger Lincoln
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25559 Salt Rock Cabell
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25560 Scott Depot Putnam
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25562 Shoals Wayne
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25564 Sod Lincoln
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25565 Spurlockville Lincoln
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25567 Sumerco Lincoln
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25569 Teays Putnam
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25570 Wayne Wayne
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25571 West Hamlin Lincoln
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25572 Woodville Boone
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25573 Yawkey Lincoln
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25601 Logan Logan
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25606 Accoville Logan
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25607 Amherstdale Logan
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25608 Baisden Mingo
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25611 Bruno Logan
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25612 Chauncey Logan
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25614 Cora Logan
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25617 Davin Logan
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25621 Gilbert Mingo
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25624 Henlawson Logan
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25625 Holden Logan
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25628 Kistler Logan
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25630 Lorado Logan
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25632 Lyburn Logan
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25634 Mallory Logan
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25635 Man Logan
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25637 Mount Gay Logan
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25638 Omar Logan
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25639 Peach Creek Logan
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25644 Sarah Ann Logan
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25646 Stollings Logan
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25647 Switzer Logan
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25649 Verdunville Logan
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25650 Verner Mingo
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25651 Wharncliffe Mingo
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25652 Whitman Logan
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25653 Wilkinson Logan
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25654 Yolyn Logan
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25661 Williamson Mingo
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25665 Borderland Mingo
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25666 Breeden Mingo
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25667 Chattaroy Mingo
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25669 Crum Wayne
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25670 Delbarton Mingo
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25671 Dingess Mingo
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25672 Edgarton Mingo
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25674 Kermit Mingo
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25676 Lenore Mingo
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25678 Matewan Mingo
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25685 Naugatuck Mingo
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25686 Newtown Mingo
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25688 North Matewan Mingo
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25690 Ragland Mingo
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25691 Rawl Mingo
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25692 Red Jacket Mingo
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25696 Varney Mingo
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25697 Vulcan Mingo
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25699 Wilsondale Wayne
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25701 Huntington Cabell
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25702 Huntington Cabell
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25703 Huntington Cabell
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25704 Huntington Wayne
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25705 Huntington Cabell
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25706 Huntington Cabell
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25707 Huntington Cabell
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25708 Huntington Cabell
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25709 Huntington Cabell
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25710 Huntington Cabell
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25711 Huntington Cabell
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25712 Huntington Cabell
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25713 Huntington Cabell
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25714 Huntington Cabell
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25715 Huntington Cabell
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25716 Huntington Cabell
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25717 Huntington Cabell
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25718 Huntington Cabell
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25719 Huntington Cabell
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25720 Huntington Cabell
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25721 Huntington Cabell
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25722 Huntington Cabell
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25723 Huntington Cabell
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25724 Huntington Cabell
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25725 Huntington Cabell
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25726 Huntington Cabell
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25727 Huntington Cabell
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25728 Huntington Cabell
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25729 Huntington Cabell
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25755 Huntington Cabell
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25770 Huntington Cabell
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25771 Huntington Cabell
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25772 Huntington Cabell
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25773 Huntington Cabell
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25774 Huntington Cabell
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25775 Huntington Cabell
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25776 Huntington Cabell
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25777 Huntington Cabell
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25778 Huntington Cabell
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25779 Huntington Cabell
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25801 Beckley Raleigh
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25802 Beckley Raleigh
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25810 Allen Junction Wyoming
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25811 Amigo Wyoming
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25812 Ansted Fayette
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25813 Beaver Raleigh
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25816 Blue Jay Raleigh
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25817 Bolt Raleigh
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25818 Bradley Raleigh
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25820 Camp Creek Mercer
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KETAMINE | FAIRFAX | ALEXANDRIA | 703-844-0184| KETAMINE THERAPY | KETAMINE AS AN ANTI-DEPRESSANT – NIH -| Dr. Sendi | Ketamine Springfield, Va | Ketamine Loudon | Ketamine for depression | email@novahealthrecovery.com

NOVA Health Recovery  <<< Ketamine infusion center in Alexandria, Virginia 703-844-0184  – consider ketamine for addiction treatment

CAll 703-844-0184 for an immediate appointment!

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

email@novahealthrecovery.com

Ketamine center in Fairfax, Virginia    << Ketamine infusions

NOVA Health Recovery – KETAMINE SYSTEMS<< Link

 

 

Here is an interesting piece regarding the rapid effects of Ketamine on reversing depression, in specific, making events more pleasurable through modulating the action of Glutamate in the brain.

This article was written by Dr. Zarate:

Ketamine and depression – NIH

Highlight: Ketamine: A New (and Faster) Path to Treating Depression

Two charts show the effect of ketamine or placebo on the Hamilton Depression Rating Scale.

Left: Change in the 21-item Hamilton Depression Rating Scale (HDRS) following ketamine or placebo treatment.
Right: Proportion of responders showing a 50 percent improvement on the HDRS following ketamine or placebo treatment.34

Source: Carlos Zarate, M.D., Experimental Therapeutics and Pathophysiology Branch, NIMH

The most commonly used antidepressants are largely variations on a theme; they increase the supply within synapses of a class of neurotransmitters believed to play a role in depression. While these drugs relieve depression for some, there is a weeks-long delay before they take effect, and some people with “treatment-resistant” depression do not respond at all.

The delay in effectiveness has suggested to scientists that the medication-induced changes in neurotransmitters are several steps away from processes more central to the root cause of depression. One possibility for a more proximal mechanism is glutamate, the primary excitatory, or activating, neurotransmitter in the brain. Preliminary studies suggested that inhibitors of glutamate could have antidepressant-like effects, and in a seminal clinical trial, the drug ketamine—which dampens glutamate signaling—lifted depression in as little as 2 hours in people with treatment-resistant depression.34

The discovery of rapidly acting antidepressants has transformed our expectations—we now look for treatments that will work in 6 hours rather than 6 weeks. But ketamine has some disadvantages; it has to be administered intravenously, the effects are transient, and it has side effects that require careful monitoring. However, results from clinical studies have confirmed the potential of the glutamate pathway as a target for the development of new antidepressants. Continuing research with ketamine has provided information on biomarkers that could be used to predict who will respond to treatment.35Clinical studies are also testing analogs of ketamine in an effort to develop glutamate inhibitors without ketamine’s side effects that can then be used in the clinic.36 Ketamine may also have potential for treating other mental illnesses; for example, a preliminary clinical trial reported that ketamine reduced the severity of symptoms in patients with PTSD. 37 Investigation of the role of glutamate signaling in other illnesses may provide the impetus to develop novel therapies based on this pathway.

One of the imperatives of clinical research going forward will be to demonstrate whether the ability of a compound to interact with a specific brain target is related to some measurable change in brain or behavioral activity that, in turn, can be associated with relief of symptoms. In a study of ketamine’s effects in patients in the depressive phase of bipolar disorder, ketamine restored pleasure-seeking behavior independent from and ahead of its other antidepressant effects. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom—loss of interest in pleasurable activities—which lasted up to 14 days.38 Brain scans traced the agent’s action to boosted activity in areas at the front and deep in the right hemisphere of the brain. This approach is consistent with the NIMH’s RDoC project, which calls for the study of functions—such as the ability to seek out and experience rewards—and their related brain systems that may identify subgroups of patients with common underlying dysfunctions that cut across traditional diagnostic categories.

The ketamine story shows that in some instances, a strong and repeatable clinical outcome stemming from a hypothesis about a specific molecular target (e.g., a glutamate receptor) can open up new arenas for basic research to explain the mechanisms of treatment response; basic studies can, in turn, provide data leading to improved treatments directed at that mechanism. A continuing focus on specific mechanisms will not only provide information on the potential of test compounds as depression medications, but will also help us understand which targets in the brain are worth aiming at in the quest for new therapies.

PET scan data superimposed on anatomical MRI

PET scans revealed that ketamine rapidly restored bipolar depressed patients’ ability to anticipate pleasurable experiences by boosting activity in the dorsal anterior cingulate cortex (yellow) and related circuitry. Picture shows PET scan data superimposed on anatomical MRI.38

References

1 Analysis based on: US Burden of Disease Collaborators. (2013). The state of US health, 1990–2010: Burden of diseases, injuries, and risk factors.JAMA, 310(6), 591–608. (PubMed ID: 23842577)

2 Walker E. R., McGee R. E., & Druss B. G. (2015). Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis.JAMA Psychiatry72(4), 334-341. (PubMed ID: 25671328)

3 Centers for Disease Control and Prevention (CDC). (2013). Web-based Injury Statistics Query and Reporting System(WISQARSTM). Atlanta, GA: National Center for Injury Prevention and Control, CDC.

4 Insel, T. R. (2008). Assessing the economic cost of serious mental illness.American Journal of Psychiatry, 165(6), 663–665. (PubMed ID: 18519528)

5 Soni, A. (2009). The five most costly conditions, 1996 and 2006: Estimates for the US civilian noninstitutionalized population (Statistical Brief# 248). Rockville, MD: Agency for Healthcare Research and Quality.

6 Murray, F. E. (2012). Evaluating the role of science philanthropy in American research universities (Working Paper No. 18146). Cambridge, MA: National Bureau of Economic Research.

7 Terry, S. F. & Terry, P. F. (2011). Power to the people: Participant ownership of clinical trial dataScience Translational Medicine3(69), 69cm3. (PubMed ID: 21307299)

8 Calculated from: McGrath, J., Saha, S., Chant, D., & Welham, J. (2008). Schizophrenia: A concise overview of incidence, prevalence, and mortalityEpidemiologic Reviews30(1), 67–76. (PubMed ID: 18480098)

9 Addington, J., Heinssen, R. K., Robinson, D. G., Schooler, N. R., Marcy, P., Brunette, M. F., … & Kane, J. M. (2015). Duration of untreated psychosis in community treatment settings in the United StatesPsychiatric Services: A Journal of the American Psychiatry Association. [Epub ahead of print] (PubMed ID: 25588418)

10 Marshall, M., Lewis, S., Lockwood, A., Drake, R., Jones, P., & Croudace, T. (2005). Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: A systematic reviewArchives of General Psychiatry62(9), 975–983. (PubMed ID: 16143729)

11 Clementz, B., Sweeney, J., Hamm J., Ivleva, E., Ethridge, L., Pearlson, G., … & Tamminga C. (2016). Identification of distinct psychosis biotypes using brain-based biomarkers.American Journal of Psychiatry. (PubMed ID: 26651391)

12 Hakamata, Y., Lissek, S., Bar-Haim, Y., Britton, J. C., Fox, N. A., Leibenluft, E., … & Pine, D. S. (2010). Attention bias modification treatment: A meta-analysis toward the establishment of novel treatment for anxiety.Biological Psychiatry68(11), 982–990. (PubMed ID: 20887977)

13 Britton, J. C., Bar‐Haim, Y., Carver, F. W., Holroyd, T., Norcross, M. A., Detloff, A., … & Pine, D. S. (2012). Isolating neural components of threat bias in pediatric anxiety.Journal of Child Psychology and Psychiatry53(6), 678–686. (PubMed ID: 22136196)

14 Lent, R., Azevedo, F. A., Andrade‐Moraes, C. H., & Pinto, A. V. (2012). How many neurons do you have? Some dogmas of quantitative neuroscience under revisionEuropean Journal of Neuroscience, 35(1), 1–9. (PubMed ID: 22151227)

15 Zhang, Y., Pak, C., Han, Y., Ahlenius, H., Zhang, Z., Chanda, S., … & Südhof, T. C. (2013). Rapid single-step induction of functional neurons from human pluripotent stem cellsNeuron78(5), 785–798. (PubMed ID: 23764284)

16 Krey, J. F., Paşca, S. P., Shcheglovitov, A., Yazawa, M., Schwemberger, R., Rasmusson, R., & Dolmetsch, R. E. (2013). Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neuronsNature Neuroscience16(2), 201–209. (PubMed ID: 23313911)

17 Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. (2011). Genome-wide association study identifies five new schizophrenia lociNature Genetics43(10), 969–976. (PubMed ID: 21926974)

18 Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2014). Biological insights from 108 schizophrenia-associated genetic lociNature511(7510), 421–427. (PubMed ID: 25056061)

19 Nishimasu, H., Ran, F.A., Hsu, P. D., Konermann, S., Shehata, S. I., Dohmae, N., … & Nureki, O. (2014). Crystal structure of Cas9 in complex with guide RNA and target DNACell156(5), 935–949. (PubMed ID: 24529477)

20 Chung, K., Wallace, J., Kim, S. Y., Kalyanasundaram, S., Andalman, A. S., Davidson, T. J., … & Deisseroth, K. (2013). Structural and molecular interrogation of intact biological systemsNature497(7449), 332–337. (PubMed ID: 23575631)

21 Colantuoni, C., Lipska, B. K., Ye, T., Hyde, T. M., Tao, R., Leek, J. T., … & Kleinman, J. E. (2011). Temporal dynamics and genetic control of transcription in the human prefrontal cortexNature, 478(7370), 519–523. (PubMed ID: 22031444)

22 Kang, H. J., Kawasawa, Y. I., Cheng, F., Zhu, Y., Xu, X., Li, M., … & Šestan, N. (2011). Spatio-temporal transcriptome of the human brainNature, 478(7370), 483–489. (PubMed ID: 22031440)

23 Li, G., Wang, L., Shi, F., Lyall, A. E., Lin, W., Gilmore, J. H., & Shen, D. (2014). Mapping longitudinal development of local cortical gyrification in infants from birth to 2 years of ageThe Journal of Neuroscience34(12), 4228–4238. (PubMed ID: 24647943)

24 Hill, J., Inder, T., Neil, J., Dierker, D., Harwell, J., & Van Essen, D. (2010). Similar patterns of cortical expansion during human development and evolutionProceedings of the National Academy of Sciences107(29), 13135–13140. (PubMed ID: 20624964)

25 Hawrylycz, M. J., Lein, E. S., Guillozet-Bongaarts, A. L., Shen, E. H., Ng, L., Miller, J. A., … & Jones, A.R. (2012). An anatomically comprehensive atlas of the adult human brain transcriptomeNature,489(7416), 391–399. (PubMed ID: 22996553)

26 Miller, J. A., Ding, S. L., Sunkin, S. M., Smith, K. A., Ng, L., Szafer, A., … & Lein, E.S. (2014). Transcriptional landscape of the prenatal human brainNature508(7495), 199–206. (PubMed ID: 24695229)

27 Willsey, A. J., Sanders, S. J., Li, M., Dong, S., Tebbenkamp, A. T., Muhle, R. A., … & State, M. W. (2013). Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autismCell155(5), 997–1007. (PubMed ID: 24267886)

28 Gulsuner, S., Walsh, T., Watts, A. C., Lee, M. K., Thornton, A. M., Casadei, S., … & McClellan, J. M. (2013). Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical networkCell154(3), 518–529. (PubMed ID: 23911319)

29 Whiteford, H. A., Degenhardt, L., Rehm, J., Baxter, A. J., Ferrari, A. J., Erskine, H. E., … & Vos, T. (2013). Global burden of disease attributable to mental and substance use disorders: Findings from the Global Burden of Disease Study 2010Lancet382(9904), 1575–1586. (PubMed ID: 23993280)

30 Insel, T. R. (2012). Next-generation treatments for mental disordersScience Translational Medicine4(155), 155ps19. (PubMed ID: 23052292)

31 Hyman, S. E. (2012). Revolution stalledScience Translational Medicine4(155), 155cm11. (PubMed ID: 23052291)

32 Biomarkers Definitions Working Group (2001). Biomarkers and surrogate endpoints: Preferred definitions and conceptual frameworkClinical Pharmacology and Therapeutics, 69(3), 89–95. (PubMed ID: 11240971)

33 McGrath, C. L., Kelley, M. E., Holtzheimer, P. E., Dunlop, B. W., Craighead, W. E., Franco, A. R., … & Mayberg, H. S. (2013). Toward a neuroimaging treatment selection biomarker for major depressive disorderJAMA Psychiatry70(8), 821–829. (PubMed ID: 23760393)

34 Zarate Jr, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., … & Manji, H. K. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depressionArchives of General Psychiatry63(8), 856–864. (PubMed ID: 16894061)

35 Cornwell, B. R., Salvadore, G., Furey, M., Marquardt, C. A., Brutsche, N. E., Grillon, C., & Zarate Jr, C. A. (2012). Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depressionBiological Psychiatry72(7), 555–561. (PubMed ID: 22521148)

36 Zarate Jr, C. A., Mathews, D., Ibrahim, L., Chaves, J. F., Marquardt, C., Ukoh, I., … & Luckenbaugh, D. A. (2013). A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depressionBiological Psychiatry,74(4), 257–264. (PubMed ID: 23206319)

37 Feder, A., Parides, M. K., Murrough, J. W., Perez, A. M., Morgan, J. E., Saxena, S., … & Charney, D. S. (2014). Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: A randomized clinical trialJAMA Psychiatry, 71(6), 681-688. (PubMed ID: 24740528)

38 Lally N., Nugent A. C., Luckenbaugh D. A., Ameli R., Roiser J. P., & Zarate C. A. (2014). Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression.Translational Psychiatry. [E-pub ahead of print] (PubMed ID: 25313512)

39 Smith, M., Saunders, R., Stuckhardt, L., & McGinnis, J. M. (Eds.). (2013). Best care at lower cost: The path to continuously learning health care in America. Washington, DC: National Academies Press. (PubMed ID: 24901184)

40 Chambers, D.A., Glasgow, R.E., & Stange, K.C. (2013). The dynamic sustainability framework: Addressing the paradox of sustainment amid ongoing change.Implementation Science, 8(1), 117. (PubMed ID: 24088228)

41 Ben-Zeev, D., Schueller, S. M., Begale, M., Duffecy, J., Kane, J. M., & Mohr, D. C. (2015). Strategies for mHealth research: Lessons from 3 mobile intervention studiesAdministration and Policy in Mental Health and Mental Health Services Research, 42(2), 157-167. (PubMed ID: 24824311)

42 Mohr, D. C., Burns, M. N., Schueller, S. M., Clarke, G., & Klinkman, M. (2013). Behavioral intervention technologies: Evidence review and recommendations for future research in mental healthGeneral Hospital Psychiatry,35(4), 332–338. (PubMed ID: 23664503)

43 Aitken, M., & Gauntlett, C. (2013). Patient apps for improved healthcare from novelty to mainstream.Parsippany, NJ: IMS Institute for Healthcare Informatics.

https://www.nimh.nih.gov/about/strategic-planning-reports/highlights/index.shtml


I also threw in a reprint of the article from NIH regarding strategic principle #2 to find biomarkers of mental health disorders:

Highlight: GPS for the Brain? BrainSpan Atlas Offers Clues to Mental Illnesses

Image from BrainSpan Atlas shows the location and expression level of the gene TGIF1 in a brain from 21 weeks postconception.

The recently created BrainSpan Atlas of the Developing Human Brain incorporates gene activity or expression (left) along with anatomical reference atlases (right) and neuroimaging data (not shown) of the mid-gestational human brain. In this figure, the location and expression level of the gene TGIF1 is shown in a brain from 21 weeks postconception.

Source: Allen Institute for Brain Science

Technologies have come a long way in mapping the trajectory of mental illnesses. Early efforts provided information on anatomical changes that occur over the course of development. In a step that has been hailed as providing a “GPS for the brain,” the BrainSpan Atlas of the Developing Brain, a partnership among the Allen Institute for Brain Science, Yale University, the University of Southern California, and NIMH—has created a comprehensive 3-D brain blueprint.25 The Atlas details not only the anatomy of the brain’s underlying structures, but also exactly where and when particular genes are turned on and off during mid-pregnancy—a time during fetal brain development when slight variations can have significant long-term consequences, including heightened risk for autism or schizophrenia.26 Knowledge of the location and time when a particular gene is turned on can help us understand how genes are disrupted in mental illnesses, providing important clues to future treatment targets and early interventions. The Atlas resources are freely available to the public on the Allen Brain Atlas data portal. Already, the BrainSpan Atlas has been used to identify genetic networks relevant to autism and schizophrenia.27,28 In both of these studies, the fetal pattern of gene expression revealed relationships that could not be detected by studying gene expression in the adult brain. As most mental illnesses are neurodevelopmental, mapping where and when genes are expressed in the brain provides a fundamental atlas for charting risk.

Brain Atlas NIH

Ketamine | Fairfax | Alexandria | 703-844-0184| Ketamine therapy | Ketamine as an anti-depressant – Is it right for you? | Dr. Sendi | Ketamine physician | Fairfax | Mt. Vernon | Harrisonburg | Virginia

NOVA Health Recovery  <<< Ketamine infusion center in Fairfax, Virginia 22306 – ketamine for depression, pain, addiction

 

Call 703-844-0184 for immediate evaluation!

I am posting a Ketamine article I published in “Your Health Magazine” below. There is excellent studies demonstrating the efficacy of Ketmine in multiple disorders, especially depression, PTSD, post-partum depression, suicidality, Obsessive-compulsive disorder, and severl other mental health problems. Likewise, Ketamine is effective in numerous painful conditions, including CRPS, neuropathy, fibromyalgia, post-herpetic neuralgia, phantom-limb pain, and others. I will discuss articles on each in the ensuing months.

I have used Ketamine over the past 20 years with excellent results in multiple settings. I have always been impressed by it’s safety, especially when it comes to respiratory and cardiac situations.

More and more information is coming about Ketamine’s versatility. Even Time magazine had a recent posting regarding it’s use in depression:

New hope in Depression

Ketamine treatment | Dr. Sendi | Fairfax | Alexandria | Virginia | 703-844-0184

Also, a mention in November JAMA 2017 with Dr. Zarate:

Abbasi J. Ketamine Minus the Trip: New Hope for Treatment-Resistant DepressionJAMA.2017;318(20):1964–1966. doi:10.1001/jama.2017.12975

Ketamine minus the trip

Ketamine minus the trip – a new hope in treating depression  < Article

Here is the audio file link regarding Ketamine in JAMA : https://jamanetwork.com/learning/audio-player/14890187

 

 

 

Ketamine has been safely used for over 45 years, serving as an effective anesthetic agent that has also been shown to have benefits in the treatment of a wide variety of painful conditions as well as mood-related disorders. Treatment-resistant depression is an example of a life-threatening disorder that can be improved through the use of specific protocols that involve the infusion of Ketamine. Depression causes tremendous suffering in both quality of life as well as medical problems that result from the stress it produces. Many individuals have tried numerous therapies that have had little to no impact on their depression, leaving them feeling hopeless over their condition. It turns out that for properly selected individuals, Ketamine can provide acute relief within hours to days. Unlike typical antidepressants, Ketamine interacts with certain brain-derived factors that encourage nerve cells to make meaningful connections that can diminish depression within a much shorter time than a standard depression medication. It is a ‘brain reset’ of sorts, allowing underlying medications to be adjusted while your mood is rapidly elevated through genuine changes of brain circuitry.

Ketamine also provides potentially effective treatment in cases of painful conditions, such as RSD/CRPS, trigeminal neuralgia, post-herpetic neuralgia, and several other nerve conditions. Ketamine can be used in an office-based intravenous protocol and then continued in a topical treatment for those who respond well.

Although Ketamine is FDA approved for anesthetic use, it has not been sent to the FDA for approval of any other medical states. However, the evidence for Ketamine’s ability to provide relief in conditions such as PTSD, anxiety disorders, depression, suicidality, post-herpetic neuralgia, CRPS, trigeminal neuralgia, and multiple other conditions has accumulated over 45 years of use in multiple studies. Ketamine is also being evaluated for drug addictions as well as alcohol use disorder. More recently, Ketamine was featured in Time magazine (August 2017) and in JAMA (November 2017) due to the  positive effects it has had in difficult-to-treat depression.

More and more clinics are offering this treatment, which creates new possibilities for improving conditions that formerly had so few options. With proper patient selection and appropriate monitoring, Ketamine can be safely and comfortably used in an office setting. With a standard slow infusion, most people do not even notice any significant side effects. If you have suffered from any of these conditions then ask your specialist if Ketamine may be a solution for you.

Pictagram from Your health magazine

Fed up with dieting? Dr. Christopher Sendi MD explains dietary success. Link in bio. • #weightloss #nutrition #exercise #washingtondc #virginia #maryland #novaaddictionspecialists #yourhealth #transformation#washingtondc #weightloss#virginia #nutrition #maryland #novaaddictionspecialists #yourhealth #exercise #transformation

“Addiction is a devastating disease that affects an individual physically and psychologically. Counseling may help the psychological component but medications can be much more effective for the physical changes that result from alcohol and opioid abuse.” – Christopher Sendi MD • Link in bio #alcoholaddiction #addiction #opioidaddiction #counseling #medication #recovery#addiction #medication #recovery#counseling #opioidaddiction #alcoholaddiction

 

 

_________________________________________________________________________________________________________________________________________

I copied an pasted an article from people’s pharmacy below that has several excellent links:

Time magazine has a cover story (August 7, 2017) titled:

“THE ANTI
ANTIDEPRESSANT

Depression afflicts 16 million Americans.
One third don’t respond to treatment
A surprising new drug may change that”

The drug in question is ketamine. Will ketamine stop suicidal thoughts better than traditional antidepressants?

When someone is suicidal seconds count!

Q. Is ketamine infusion safe for the elderly? My son’s mother-in-law (age 69) has been diagnosed with major depression. She has made two suicide attempts.

I am not sure what she is taking now, but she seems apathetic, worries about everything and interacts inappropriately with family. She is almost completely unresponsive to her grandchildren. This is a total change from her personality five years ago, when she was devoted to her family and engaged with the world.

A. Major depression takes a terrible toll on the individual, family and friends. Suicide attempts are a clear signal that your son’s mother-in-law is desperate and requires expert medical intervention.

Ketamine (Ketalar) is a fascinating drug that has been used since 1962 as a general anesthetic. Over the last several years researchers have discovered that this medication has profound antidepressant activity that kicks in within hours instead of the usual weeks of standard drugs. When someone is suicidal it is dangerous to wait weeks for an antidepressant drug to work.

Will Ketamine Stop Suicidal Thoughts?

A recent meta-analysis found that ketamine is effective in reducing suicidal ideation within four hours (Neuroscience and Biobehavioral Reviews, June 2017).  Unfortunately, research has not yet shown how long this effect may last.

This isn’t the first assessment of ketamine in the treatment of suicidal thoughts.

Here are some other reports in the medical literature:

“Sublingual (under the tongue) Ketamine for Rapid Relief of Suicidal Ideation”:

“These cases demonstrate that low doses of sublingual ketamine repeated over a span of hours can induce rapid remission of suicidality in unipolar or bipolar depression.

“Chronic use of oral or sublingual ketamine has been helpful in the past 4 years for many of my patients with mild depressive symptoms.

“Sublingual ketamine may be a practical option for managing suicidality in outpatients as an adjunct to traditional antidepressants and mood stabilizers and could shorten the hospital stay of psychiatric inpatients. Sublingual ketamine is worthy of systematic study as a treatment to provide rapid relief of suicidal ideation.”

Reduction in Suicidal Ideation Following Repeated Doses of Intravenous Ketamine?

…”the evidence to date supporting the clinical use of ketamine as antisuicidal treatment is extremely preliminary, and on the basis of the article by Ionescu et al, conclusions concerning the effects of ketamine on suicidal ideation should be drawn with caution.”

Ketamine Rapidly Relieves Acute Suicidal Ideation in Cancer Patients: A Randomized Controlled Clinical Trial

“Cancer patients experience increased risk and incidence of suicide and other psychiatric disorders.

“In the past 10 years, evidence has emerged showing that sub-anesthetic doses of ketamine (0.5 mg/kg) induce fast-acting antidepressant effects on depressed patients. Antidepressant effects of ketamine were observed as soon as 40 min after infusion and typically lasted at most for 7 days, with some patients experiencing more prolonged mood improvement.

” Collectively, this study provides novel information about the rapid antidepressant effect of ketamine on acute depression and suicidal ideation in newly-diagnosed cancer patients.”

“Ketamine for Treatment of Suicidal Ideation and Reduction of Risk for Suicidal Behavior”

(in Current Psychiatry Reports, June, 2016).

“Our review concludes that ketamine treatment can be seen as a double-edged sword, clinically to help provide treatment for acutely suicidal patients and experimentally to explore the neurobiological nature of suicidal ideation and suicidal behavior.”

Ketamine and Your Mother-In-Law:

There is inadequate research on ketamine infusion in older patients (Expert Opinion on Pharmacotherapy, April 2017).  Since this medication may alter blood pressure and heart rate, the latest recommendations from the American Psychiatric Association call for monitoring so that immediate care may be provided if necessary (JAMA Psychiatry, April 1, 2017).

More articles from The People’s Pharmacy about whether Ketamine can stop suicidal thoughts are available at these links:

Can Ketamine Jump Start Antidepressant Action?

Radio Show # 983 (FREE): Intriguing Approaches to Overcoming Depression

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Dr. Sendi graduated from Georgetown University Medical School and trained at Pitt County Memorial Hospital, East Carolina University, Greenville, N.C. for his Board Certification in Internal Medicine. He is also ABPSUS Board Certified in Emergency Medicine and Board Certified in Obesity Medicine with the American Board of Obesity Medicine.

Practice Philosophy

NOVA Health Recovery was founded to provide the optimal care to patients suffering from life-altering, preventable illnesses such as Obesity, Addiction, and Pain. We provide progressive therapies for challenging cases of depression, PTSD, neuropathy, CRPS/RSD, and other painful conditions using Ketamine infusions in a comfortable and safely monitored setting. We also use state-of-the-art interventions for addictions of multiple types, providing the tools and support to allow one to move forward in a healthy, successful manner. There is no need to suffer from treatable conditions in which progressive medication assisted therapies, behavioral support, wellness plans, and general health screening can allow you to improve your quality of life. We also use telemedicine to make it easy for you to see your physician from the comfort of your own home.

Professional Memberships:

American College of Physicians, American Society of Addiction Medicine, American Society for Nutrition, The Obesity Society.

Special Interests:

Dr. Sendi has 21 years experience in the medical field. Included experiences are Addiction and Pain Management, Obesity and weight management, lipidology, and wellness. Dr. Sendi is Board Certified in Internal Medicine, Emergency Medicine, and Obesity Medicine. His additional interests include wellness, aging, and health-risk mitigation.

Have you Tried all options for depression and pain?

At NOVA Health Recovery, we understand how painful conditions, such as CRPS, post-herpetic neuralgia, and neuropathies rob your life of comfort and quality. We also recognize the suffering that mental health problems, such as anxiety, depression, and PTSD inflict on people and destroy the ability to enjoy even their best years. Many have exhausted multiple therapies and feel hopeless about any treatment at all. NOVA Health Recovery offers Ketamine treatments to appropriate patients who suffer such conditions. In conjunction with other regimens, Ketamine infusion, offered in a monitored, comfortable setting, may provide improvement. This option may just be what you need to pick up your mood and decrease you pain while your regular medications take effect.

Want to learn more? Schedule a consultation today by calling 703-844-0184.