Ketamine Therapy | Ketamine Doctors | 703-844-0184 | Fairfax, Virginia | Depression causes RAPID AGING due to Oxidative stress | NOVA Health Recovery, Alexandria, Va 22306

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Reasons to treat depression rapidly – Depression causes rapid aging> Consider using a rapid – acting antidepressant!

Depression ‘makes us biologically older’  BBC Article

Major depressive disorder and accelerated cellular aging

Patients with major depressive disorder (MDD) have an increased onset risk of aging-related somatic diseases such as heart disease,
diabetes, obesity and cancer. This suggests mechanisms of accelerated biological aging among the depressed, which can be
indicated by a shorter length of telomeres. We examine whether MDD is associated with accelerated biological aging, and whether
depression characteristics such as severity, duration, and psychoactive medication do further impact on biological aging. Data are
from the Netherlands Study of Depression and Anxiety, including 1095 current MDD patients, 802 remitted MDD patients and 510
control subjects. Telomere length (TL) was assessed as the telomere sequence copy number (T) compared to a single-copy gene
copy number (S) using quantitative polymerase chain reaction. This resulted in a T/S ratio and was converted to base pairs (bp).
MDD diagnosis and MDD characteristics were determined by self-report questionnaires and structured psychiatric interviews.
Compared with control subjects (mean bp = 5541), sociodemographic-adjusted TL was shorter among remitted MDD patients
(mean bp = 5459; P = 0.014) and current MDD patients (mean bp = 5461; P = 0.012). Adjustment for health and lifestyle variables did
not reduce the associations. Within the current MDD patients, separate analyses showed that both higher depression severity
(P<0.01) and longer symptom duration in the past 4 years (P = 0.01) were associated with shorter TL. Our results demonstrate that
depressed patients show accelerated cellular aging according to a ‘dose–response’ gradient: those with the most severe and
chronic MDD showed the shortest TL. We also confirmed the imprint of past exposure to depression, as those with remitted MDD
had shorter TL than controls

In this large cohort study we demonstrated that currently
depressed persons had shorter TL than never-depressed controls.
Based on an estimated mean telomere shortening rate of 14–20
bp per year as found in this and other studies,20,23,26 the
differences observed indicate 4–6 years of accelerated aging for
the current MDD sample as compared to controls. We also showed
evidence for the imprint of past exposure to depression since
those with remitted MDD also had shorter TL than control
subjects. These observed associations remained significant after
controlling for lifestyle and somatic health variables, suggesting that the shortened telomeres were not simply due to unhealthylifestyle or poorer somatic health among depressed persons.
Finally, the association between MDD and TL showed a ‘dose–
response’ gradient, since the most severely and chronically
depressed patients had the shortest telomeres.

MDD is thus associated with shortened TL, which resembles
accelerated biological aging. The disorder has previously also been
associated with dysregulations of the hypothalamus–pituitary–
adrenal (HPA) axis,43,45 the immune system,46,47 the autonomic
nervous system (ANS)48,49 and increased oxidative stress.50
Shortened telomeres, in turn, are suggested to be a consequence
or a concomitant of these dysregulated biological stress systems.
In line with this, several in vitro and in vivo studies found increased
cortisol,51 oxidative stress52 and pro-inflammatory cytokines53
to be associated with shorter TL. Dysregulations of these stress systems could contribute to telomere shortening in MDD patients.9,12
However, the exact biological mechanisms that mediate the relation
between depression and telomere shortening, as well as the
direction of the link, remain to be further explored.

Oxidative stress shortens telomeres

Elevated DNA Oxidation and DNA Repair Enzyme Expression in Brain White Matter in Major Depressive Disorder.

The Role of Oxidative Stress in Depressive Disorders

Abstract:

Studies of the World Health Organization suggest that in the year 2020, depressive disorder will be the illness with the highest
burden of disease. Especially unipolar depression is the psychiatric disorder with the highest prevalence and incidence, it is cost-intensive and has a relatively high morbidity. Lately, the biological process involved in the aetiology of depression has been the focus of research.
Since its emergence, the monoamine hypothesis has been adjusted and extended considerably. An increasing body of evidence points to
alterations not only in brain function, but also in neuronal plasticity. The clinical presentations demonstrate these dysfunctions by accompanying cognitive symptoms such as problems with memory and concentration. Modern imaging techniques show volume reduction of the hippocampus and the frontal cortex. These findings are in line with post-mortem studies of patients with depressive disorder and they point to a significant decrease of neuronal and glial cells in cortico-limbic regions which can be seen as a consequence of alterations in
neuronal plasticity in this disorder. This could be triggered by an increase of free radicals which in turn eventually leads to cell death and consequently atrophy of vulnerable neuronal and glial cell population in these regions. Therefore, research on increased oxidative stress in unipolar depressive disorder, mediated by elevated concentrations of free radicals, has been undertaken. This review gives a comprehensive overview over the current literature discussing the involvement of oxidative stress and free radicals in depression.

Membrane damage in blood of patients with depression has
been shown by elevated of omega 3- fatty-acids [45] and by increased
lipid peroxidation products in patients with DD [42, 45,
[46, 47]. Furthermore, DNA-strand brakes have been reported in
the blood of these patients [48]. DD has been linked to increased
serum levels of malondialdehyde (MDA), a breakdown product of
oxidized apolipoprotein B-containing lipoproteins, and thus a
marker of the rate of peroxide breakdown [49, 50].

In patients with DD (Depressive Disorders), elevated levels of MDA adversely affect
the efficiency of visual-spatial and auditory-verbal working memory,
short-term declarative memory and delayed recall declarative
memory [51]. Higher concentration of plasma MDA in patients
with recurrent depression is associated with the severity of depressive
symptoms, both at the beginning of antidepressant pharmacotherapy,
and after 8 weeks of treatment. Statistically significant
differences were found in the intensity of depressive symptoms,
measured on therapy onset versus the examination results after
8 weeks of treatment [51]. Although this is used as a marker of lipid peroxidation, it is considered to be less stable than 8-iso-PGF2a, and more susceptible to confounding factors such as antioxidants from diet [52]. Therefore, the best way to investigate oxidative disruptions to lipids in humans is via assessing levels of F2-
isoprostanes [52-54]. These are stable compounds produced in the
process of lipid peroxidation [52, 54]. 8-iso-PGF2a are specific F2-
isoprostane molecules produced during the peroxidation of arachnidonic acid. However, the mean serum level of 8-iso-PGF2a was shown to be significantly higher in a group of patients with DD,
controlling for lifestyle variables such as body mass index, alcohol
consumption, and physical activity [55, 56]. Cerebral membrane
abnormalities and altered membrane phospholipids have been suggested by an increased choline-containing compound seen in the
putamen of patients with DD [57] which has been interpreted as a
result of increased oxidative stress in patients with DD.

A Meta-Analysis of Oxidative Stress Markers in Depression

Results
115 articles met the inclusion criteria. Lower TAC was noted in acute episodes (AEs) of depressed patients (p<0.05). Antioxidants, including serum paraoxonase, uric acid, albumin,
high-density lipoprotein cholesterol and zinc levels were lower than controls (p<0.05); the serum uric acid, albumin and vitamin C levels were increased after antidepressant therapy
(p<0.05). Oxidative damage products, including red blood cell (RBC) malondialdehyde (MDA), serum MDA and 8-F2-isoprostanes levels were higher than controls (p<0.05). After
antidepressant medication, RBC and serum MDA levels were decreased (p<0.05). Moreover, serum peroxide in free radicals levels were higher than controls (p<0.05). There were
no difference

Conclusion
This meta-analysis supports the facts that the serum TAC, paraoxonase and antioxidant levels are lower, and the serum free radical and oxidative damage product levels are higher
than controls in depressed patients. Meanwhile, the antioxidant levels are increased and the oxidative damage product levels are decreased after antidepressant medication. The
pathophysiological relationships between oxidative stress and depression, and the potential benefits of antioxidant supplementation deserve further research.

Some studies have demonstrated that depressed patients’ oxidative product levels in their peripheral blood [3, 4], red blood cells (RBC) [4], mononuclear cells [5], urine [6], cerebrospinal
fluid [7] and postmortem brains [8] were abnormal. Antioxidant system disturbance in peripheral blood has also been reported [9]. Autoimmune responses against neoepitopes
induced by oxidative damage of fatty acid and protein membranes have been reported [10, 11].
Lower glutathione (GSH) levels [12] and a negative relationship between anhedonia severity
and occipital GSH levels [13] were found through magnetic resonance spectroscopy (MRS).

Oxidative stress is defined as a persistent imbalance between oxidation and anti-oxidation, which leads to the damage of cellular macromolecules [14, 15]. The free radicals consist of reactive
oxygen species (ROS) and reactive nitrogen species (RNS). The main ROS includes superoxide anion, hydroxy radical and hydrogen peroxide, and the RNS consists of nitric oxide
(NO), nitrogen dioxide and peroxynitrite. Nitrite is often used as a marker of NO activity. Interestingly, the brain appears to be more susceptible to the ROS/RNS because of the high
content of unsaturated fatty acids, high oxygen consumption per unit weight, high content of key ingredients of lipid peroxidation (LP) and scarcity of antioxidant defence systems [16].
The oxidative products include products of oxidative damage of LP, protein and DNA in depression. As a product of LP, abnormal malondialdehyde (MDA) levels in depression have
been reported [17]. 8-F2-isoprostane (8-iso-PGF2α) is another product of LP [18] that is considered
to be a marker of LP because of its chemical stability [19]. The protein carbonyl (PC), 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-oxo-7, 8-dihydroguanosine (8-oxoGuo) are
the markers of protein, DNA and RNA oxidative damage, respectively [3, 20, 21]. The oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to the generation of new epitopes modified (neoepitopes). The antibodies against oxidative neoepitopes
in depression have been found [10, 11, 22–24]. On the other hand, the antioxidant defence systems can be divided into enzymatic and non-enzymatic antioxidants. The nonenzymatic
antioxidants include vitamins C and E, albumin, uric acid, high-density lipoprotein cholesterol (HDL-C), GSH, coenzyme Q10 (CoQ10), ceruloplasmin, zinc, selenium, and so on.
The enzymatic antioxidants include superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), glutathione reductase (GR), paraoxonase 1 (PON1), and so on.

Discussion
The present findings support oxidative stress may be disordered in depressed patients, which is demonstrated by abnormal oxidative stress marker levels. In this meta-analysis, at first we
found in depressed patients: 1) the serum TAC, PON, uric acid, albumin, HDL-C and zinc levels were lower than controls; 2) the serum peroxide, MDA, 8-iso-PGF2α and RBC MDA levels
were higher than controls. To explore the effect of the antidepressant therapy to oxidative stress
markers, we reviewed the studies which had changes. And it came to the conclusions: 1) the serum uric acid, albumin, and vitamin C levels were increased; 2) the serum nitrite, RBC and
serum MDA levels were decreased.

The serum antioxidant levels are significantly lower in depression in our study and previous
reports, including PON, albumin, zinc, uric acid HDL-C, CoQ10 [146] and GSH [4, 38].
Meanwhile, the oxidative damage product levels are significantly higher. The body couldn’t
scavenge the excess free radicals (peroxide), leading to damages of main parts of cellular macromolecules
such as fatty acids, protein, DNA, RNA and mitochondria. The longitudinal antidepressant
therapy can reverse these abnormal oxidative stress parameters. It has proved
these phenomena occur in depression, such as increased levels of MDA, 8-iso-PGF2α, 8-oxoGuo
and 8-OHdG [3, 21]. Oxidative stress plays a crucial role in the pathophysiology of
depression. Some genes may be a potential factor. Lawlor et al (2007) reported the R allele of
PON1Q192R was associated with depression [147]. In addition, poor appetite, psychological
stressors, obesity, metabolic syndrome, sleep disorders, cigarette smoking and unhealthy lifestyle
may also contribute to it [148]. Furthermore, oxidative stress activates the immuneinflammatory
pathways [148]. But some studies supported decrease in albumin, zinc and
HDL-C levels was probably related to increased levels of pro-inflammatory cytokines (such as
interleukin-1 (IL-1) and IL-6) [59, 70–72, 117] during an acute phase response, which illustrated the activated immune-inflammatory pathways also activates the oxidative stress. These two mechanisms influence each other. On the other hand, the oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to generation of newepitopes modified (neoepitopes). Oxidative neoepitopes reported up to now include the conjugated oleic and azelaic acid, MDA, phosphatidyl inositol (Pi), NO-modified adducts and oxidized low density lipoprotein (oxLDL) [11, 22–24]. Maes et al reported the levels of serum IgG antibody against the oxLDL and IgM antibodies against the conjugated oleic and azelaic acid, MDA, Pi and NO-modified adducts were increased in depression [11, 22–24]. Depleted antioxidant defence in depression suggests that antioxidant supplements may be useful in clinical management. Preliminary evidence has indicated that patients treated with CoQ10 showed improvement in depressive symptoms and decrease in hippocampal oxidative DNA damage [149]. In our analyses, vitamin C and E levels did not differ between depressed patients and controls, but many studies have reported that vitamin C and E supplements could improve depressive moods [150, 151].

Malondialdehyde plasma concentration correlates with declarative and working memory in patients with recurrent depressive disorder

Abstract

Oxidative stress has been implicated in the cognitive decline, especially in memory impairment. The purpose of this study was to determine the concentration of malondialdehyde (MDA) in patients with recurrent depressive disorders (rDD) and to define relationship between plasma levels of MDA and the cognitive performance. The study comprised 46 patients meeting criteria for rDD. Cognitive function assessment was based on: The Trail Making Test , The Stroop Test, Verbal Fluency Test and Auditory-Verbal Learning Test. The severity of depression symptoms was assessed using the Hamilton Depression Rating Scale (HDRS). Statistically significant differences were found in the intensity of depression symptoms, measured by the HDRS on therapy onset versus the examination results after 8 weeks of treatment (P < 0.001). Considering the 8-week pharmacotherapy period, rDD patients presented better outcomes in cognitive function tests. There was no statistically significant correlation between plasma MDA levels, and the age, disease duration, number of previous depressive episodes and the results in HDRS applied on admission and on discharge. Elevated levels of MDA adversely affected the efficiency of visual-spatial and auditory-verbal working memory, short-term declarative memory and the delayed recall declarative memory. 1. Higher concentration of plasma MDA in rDD patients is associated with the severity of depressive symptoms, both at the beginning of antidepressants pharmacotherapy, and after 8 weeks of its duration. 2. Elevated levels of plasma MDA are related to the impairment of visual-spatial and auditory-verbal working memory and short-term and delayed declarative memory.

Antioxidant /Antidepressant-like Effect of Ascorbic acid (Vitamine
C) and Fluoxetine
Another study investigated the influence of ascorbic acid
(which is an antioxidant with antidepressant-like effects in animals)
on both depressive-like behaviour induced by a chronic unpredictable
stress (CUS) paradigm and on serum markers of oxidative
stress and in cerebral cortex and hippocampus of mice [120]. The
CUS-model is an animal model for induced depression-like behaviour
in animals. Depressive-like behaviour induced by CUS was
accompanied by significantly increased lipid peroxidation (cerebral
cortex and hippocampus), decreased catalase (CAT) (cerebral cortex
and hippocampus) and glutathione reductase (GR) (hippocampus)
activities and reduced levels of glutathione (cerebral cortex).
Repeated ascorbic acid as well as fluoxetine administration significantly
reversed CUS-induced depressive-like behaviour as well as
oxidative damage. No alterations were observed in locomotor activity
and glutathione peroxidase (GPx) activity in the same sample.
These findings pointed to a rapid and robust effect of ascorbic acid
in reversing behavioural and biochemical alterations induced in an
animal model [120].  Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress.

 

Ketamine Therapy | Ketamine Doctors | 703-844-0184 | Fairfax, Virginia | Ketamine and Psychedelic drugs – for depression and neuroplasticity | NOVA Health Recovery, Alexandria, Va 22306

NOVA Health Recovery  <<< Ketamine Treatment Center Fairfax, Virginia

CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

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

email@novahealthrecovery.com  << Email for questions to the doctor

Ketamine center in Fairfax, Virginia    << Ketamine infusions

Ketamine – NOVA Ketamine facebook page – ketamine treatment for depression

facebook Ketamine page

NOVA Health Recovery  << Ketamine clinic Fairfax, Va  – Call 703-844-0184 for an appointment – Fairfax, Virginia

Ketamine Consultants Blog
_______________________________________________________________________________________________


Ketamine and Psychedelic Drugs Change Structure of Neurons

ummary: A new study reveals psychedelics increase dendrites, dendritic spines and synapses, while ketamine may promote neuroplasticity. The findings could help develop new treatments for anxiety, depression and other related disorders.

Source: UC Davis.

A team of scientists at the University of California, Davis is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety, and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

Fairfax | NOVA Ketamine IV Ketamine for depression | Fairfax, Va 22306 | 703-844-0184
Fairfax | NOVA Ketamine IV Ketamine for depression | Fairfax, Va 22306 | 703-844-0184

Ketamine and Psychedelic Drugs Change Structure of Neurons

Summary: A new study reveals psychedelics increase dendrites, dendritic spines and synapses, while ketamine may promote neuroplasticity. The findings could help develop new treatments for anxiety, depression and other related disorders.

Source: UC Davis.

A team of scientists at the University of California, Davis is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety, and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

image shows neurons under psychedelics and ketamine

Psychedelic drugs such as LSD and ayahuasca change the structure of nerve cells, causing them to sprout more branches and spines, UC Davis researchers have found. This could help in “rewiring” the brain to treat depression and other disorders. In this false-colored image, the rainbow-colored cell was treated with LSD compared to a control cell in blue. NeuroscienceNews.com image is credited to Calvin and Joanne Ly.

Behavioral studies also hint at the similarities between psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder (PTSD), and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.

These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.

“Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives,” Olson said.

 

Psychedelic drugs, ketamine change structure of neurons

Psychedelic drugs, ketamine change structure of neurons

Psychedelics as Possible Treatments for Depression and PTSD

A team of scientists at the University of California, Davis, is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety and related disorders.

In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines) and the number of connections between neurons (synapses). These structural changes could suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

Behavioral studies also hint at the similarities between psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder, or PTSD, and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.

These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.

“Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives,” Olson said.

Additional co-authors on the Cell Reports “Psychedelics Promote Structural and Functional Neural Plasticity.” study are Calvin Ly, Alexandra Greb, Sina Soltanzadeh Zarandi, Lindsay Cameron, Jonathon Wong, Eden Barragan, Paige Wilson, Michael Paddy, Kassandra Ori-McKinney, Kyle Burbach, Megan Dennis, Alexander Sood, Whitney Duim, Kimberley McAllister and John Gray.

Olson and Cameron were co-authors on the ACS Chemical Neuroscience paper along with Charlie Benson and Lee Dunlap.

The work was partly supported by grants from the National Institutes of Health.

Psychedelics Promote Structural and Functional
Neural Plasticity

Below is the Intro and Discussion for the article:

Psychedelics Promote Structural and Functional neural Plasticity

Authors:

Calvin Ly, Alexandra C. Greb,
Lindsay P. Cameron, …,
Kassandra M. Ori-McKenney,
John A. Gray, David E. Olson
Correspondence
deolson@ucdavis.edu

In Brief
Ly et al. demonstrate that psychedelic
compounds such as LSD, DMT, and DOI
increase dendritic arbor complexity,
promote dendritic spine growth, and
stimulate synapse formation. These
cellular effects are similar to those
produced by the fast-acting
antidepressant ketamine and highlight
the potential of psychedelics for treating
depression and related disorders.

  • Highlights
     Serotonergic psychedelics increase neuritogenesis,
    spinogenesis, and synaptogenesis
  •  Psychedelics promote plasticity via an evolutionarily
    conserved mechanism
  •  TrkB, mTOR, and 5-HT2A signaling underlie psychedelicinduced
    plasticity
  •  Noribogaine, but not ibogaine, is capable of promoting
    structural neural plasticity

SUMMARY
Atrophy of neurons in the prefrontal cortex (PFC)
plays a key role in the pathophysiology of depression
and related disorders. The ability to promote
both structural and functional plasticity in the PFC
has been hypothesized to underlie the fast-acting
antidepressant properties of the dissociative anesthetic
ketamine. Here, we report that, like ketamine,
serotonergic psychedelics are capable of robustly
increasing neuritogenesis and/or spinogenesis both
in vitro and in vivo. These changes in neuronal structure
are accompanied by increased synapse number
and function, as measured by fluorescence microscopy
and electrophysiology. The structural changes
induced by psychedelics appear to result from stimulation
of the TrkB, mTOR, and 5-HT2A signaling
pathways and could possibly explain the clinical
effectiveness of these compounds. Our results underscore
the therapeutic potential of psychedelics
and, importantly, identify several lead scaffolds for
medicinal chemistry efforts focused on developing
plasticity-promoting compounds as safe, effective,
and fast-acting treatments for depression and
related disorders.

INTRODUCTION
Neuropsychiatric diseases, including mood and anxiety disorders,
are some of the leading causes of disability worldwide
and place an enormous economic burden on society (Gustavsson
et al., 2011; Whiteford et al., 2013). Approximately
one-third of patients will not respond to current antidepressant
drugs, and those who do will usually require at least 2–4 weeks
of treatment before they experience any beneficial effects
(Rush et al., 2006). Depression, post-traumatic stress disorder
(PTSD), and addiction share common neural circuitry (Arnsten,
2009; Russo et al., 2009; Peters et al., 2010; Russo and
Nestler, 2013) and have high comorbidity (Kelly and Daley,
2013). A preponderance of evidence from a combination of
human imaging, postmortem studies, and animal models suggests
that atrophy of neurons in the prefrontal cortex (PFC)
plays a key role in the pathophysiology of depression and
related disorders and is precipitated and/or exacerbated by
stress (Arnsten, 2009; Autry and Monteggia, 2012; Christoffel
et al., 2011; Duman and Aghajanian, 2012; Duman et al.,
2016; Izquierdo et al., 2006; Pittenger and Duman, 2008;
Qiao et al., 2016; Russo and Nestler, 2013). These structural
changes, such as the retraction of neurites, loss of dendritic
spines, and elimination of synapses, can potentially be counteracted
by compounds capable of promoting structural and
functional neural plasticity in the PFC (Castre´ n and Antila,
2017; Cramer et al., 2011; Duman, 2002; Hayley and Litteljohn,
2013; Kolb and Muhammad, 2014; Krystal et al., 2009;
Mathew et al., 2008), providing a general solution to treating
all of these related diseases. However, only a relatively small
number of compounds capable of promoting plasticity in the
PFC have been identified so far, each with significant drawbacks
(Castre´ n and Antila, 2017). Of these, the dissociative
anesthetic ketamine has shown the most promise, revitalizing
the field of molecular psychiatry in recent years.
Ketamine has demonstrated remarkable clinical potential as a
fast-acting antidepressant (Berman et al., 2000; Ionescu et al.,
2016; Zarate et al., 2012), even exhibiting efficacy in treatmentresistant
populations (DiazGranados et al., 2010; Murrough
et al., 2013; Zarate et al., 2006). Additionally, it has shown promise
for treating PTSD (Feder et al., 2014) and heroin addiction
(Krupitsky et al., 2002). Animal models suggest that its therapeutic
effects stem from its ability to promote the growth of dendritic
spines, increase the synthesis of synaptic proteins, and
strengthen synaptic responses (Autry et al., 2011; Browne and
Lucki, 2013; Li et al., 2010).

Like ketamine, serotonergic psychedelics and entactogens
have demonstrated rapid and long-lasting antidepressant and
anxiolytic effects in the clinic after a single dose (Bouso et al.,
2008; Carhart-Harris and Goodwin, 2017; Grob et al., 2011;
Mithoefer et al., 2013, 2016; Nichols et al., 2017; Sanches
et al., 2016; Oso´ rio et al., 2015), including in treatment-resistant
populations (Carhart-Harris et al., 2016, 2017; Mithoefer et al.,
2011; Oehen et al., 2013; Rucker et al., 2016). In fact, there
have been numerous clinical trials in the past 30 years examining
the therapeutic effects of these drugs (Dos Santos et al., 2016),
with 3,4-methylenedioxymethamphetamine (MDMA) recently
receiving the ‘‘breakthrough therapy’’ designation by the Food
and Drug Administration for treating PTSD. Furthermore, classical
psychedelics and entactogens produce antidepressant
and anxiolytic responses in rodent behavioral tests, such as
the forced swim test (Cameron et al., 2018) and fear extinction
learning (Cameron et al., 2018; Catlow et al., 2013; Young
et al., 2015), paradigms for which ketamine has also been shown
to be effective (Autry et al., 2011; Girgenti et al., 2017; Li et al.,
2010). Despite the promising antidepressant, anxiolytic, and
anti-addictive properties of serotonergic psychedelics, their
therapeutic mechanism of action remains poorly understood,
and concerns about safety have severely limited their clinical
usefulness.
Because of the similarities between classical serotonergic
psychedelics and ketamine in both preclinical models and clinical
studies, we reasoned that their therapeutic effects might
result from a shared ability to promote structural and functional
neural plasticity in cortical neurons. Here, we report that serotonergic
psychedelics and entactogens from a variety of chemical
classes (e.g., amphetamine, tryptamine, and ergoline) display
plasticity-promoting properties comparable to or greater than
ketamine. Like ketamine, these compounds stimulate structural
plasticity by activating the mammalian target of rapamycin
(mTOR). To classify the growing number of compounds capable
of rapidly promoting induced plasticity (Castre´ n and Antila,
2017), we introduce the term ‘‘psychoplastogen,’’ from the
Greek roots psych- (mind), -plast (molded), and -gen (producing).
Our work strengthens the growing body of literature indicating
that psychoplastogens capable of promoting plasticity
in the PFC might have value as fast-acting antidepressants
and anxiolytics with efficacy in treatment-resistant populations
and suggests that it may be possible to use classical psychedelics
as lead structures for identifying safer alternatives.

DISCUSSION
Classical serotonergic psychedelics are known to cause
changes in mood (Griffiths et al., 2006, 2008, 2011) and brain
function (Carhart-Harris et al., 2017) that persist long after the
acute effects of the drugs have subsided. Moreover, several
psychedelics elevate glutamate levels in the cortex (Nichols,
2004, 2016) and increase gene expression in vivo of the neurotrophin
BDNF as well as immediate-early genes associated with
plasticity (Martin et al., 2014; Nichols and Sanders-Bush, 2002;
Vaidya et al., 1997). This indirect evidence has led to the
reasonable hypothesis that psychedelics promote structural
and functional neural plasticity, although this assumption had
never been rigorously tested (Bogenschutz and Pommy,
2012; Vollenweider and Kometer, 2010). The data presented
here provide direct evidence for this hypothesis, demonstrating
that psychedelics cause both structural and functional changes
in cortical neurons.

Prior to this study, two reports suggested
that psychedelics might be able
to produce changes in neuronal structure.
Jones et al. (2009) demonstrated that DOI
was capable of transiently increasing the
size of dendritic spines on cortical neurons,
but no change in spine density was
observed. The second study showed
that DOI promoted neurite extension in a
cell line of neuronal lineage (Marinova
et al., 2017). Both of these reports utilized
DOI, a psychedelic of the amphetamine
class. Here we demonstrate that the ability
to change neuronal structure is not a
unique property of amphetamines like
DOI because psychedelics from the ergoline,
tryptamine, and iboga classes of compounds also promote
structural plasticity. Additionally, D-amphetamine does not increase
the complexity of cortical dendritic arbors in culture,
and therefore, these morphological changes cannot be simply
attributed to an increase in monoamine neurotransmission.
The identification of psychoplastogens belonging to distinct
chemical families is an important aspect of this work because
it suggests that ketamine is not unique in its ability to promote
structural and functional plasticity. In addition to ketamine, the
prototypical psychoplastogen, only a relatively small number of
plasticity-promoting small molecules have been identified previously.
Such compounds include the N-methyl-D-aspartate
(NMDA) receptor ligand GLYX-13 (i.e., rapastinel), the mGlu2/3
antagonist LY341495, the TrkB agonist 7,8-DHF, and the muscarinic
receptor antagonist scopolamine (Lepack et al., 2016; Castello
et al., 2014; Zeng et al., 2012; Voleti et al., 2013). We
observe that hallucinogens from four distinct structural classes
(i.e., tryptamine, amphetamine, ergoline, and iboga) are also
potent psychoplastogens, providing additional lead scaffolds
for medicinal chemistry efforts aimed at identifying neurotherapeutics.
Furthermore, our cellular assays revealed that several
of these compounds were more efficacious (e.g., MDMA) or more potent (e.g., LSD) than ketamine. In fact, the plasticity-promoting
properties of psychedelics and entactogens rivaled that
of BDNF (Figures 3A–3C and S3). The extreme potency of LSD
in particular might be due to slow off kinetics, as recently proposed
following the disclosure of the LSD-bound 5-HT2B crystal
structure (Wacker et al., 2017).
Importantly, the psychoplastogenic effects of psychedelics in
cortical cultures were also observed in vivo using both vertebrate
and invertebrate models, demonstrating that they act through an
evolutionarily conserved mechanism. Furthermore, the concentrations
of psychedelics utilized in our in vitro cell culture assays
were consistent with those reached in the brain following systemic
administration of therapeutic doses in rodents (Yang
et al., 2018; Cohen and Vogel, 1972). This suggests that neuritogenesis,
spinogenesis, and/or synaptogenesis assays performed
using cortical cultures might have value for identifying
psychoplastogens and fast-acting antidepressants. It should
be noted that our structural plasticity studies performed in vitro
utilized neurons exposed to psychedelics for extended periods
of time. Because brain exposure to these compounds is often
of short duration due to rapid metabolism, it will be interesting
to assess the kinetics of psychedelic-induced plasticity.
A key question in the field of psychedelic medicine has been
whether or not psychedelics promote changes in the density of
dendritic spines (Kyzar et al., 2017). Using super-resolution
SIM, we clearly demonstrate that psychedelics do, in fact, increase
the density of dendritic spines on cortical neurons, an effect
that is not restricted to a particular structural class of compounds.
Using DMT, we verified that cortical neuron spine
density increases in vivo and that these changes in structural
plasticity are accompanied by functional effects such as
increased amplitude and frequency of spontaneous EPSCs.

We specifically designed these experiments
to mimic previous studies of ketamine
(Li et al., 2010) so that we might
directly compare these two compounds,
and, to a first approximation, they appear
to be remarkably similar. Not only do they
both increase spine density and neuronal
excitability in the cortex, they seem to
have similar behavioral effects. We have
shown previously that, like ketamine,
DMT promotes fear extinction learning
and has antidepressant effects in the
forced swim test (Cameron et al., 2018). These results, coupled
with the fact that ayahuasca, a DMT-containing concoction, has
potent antidepressant effects in humans (Oso´ rio et al., 2015;
Sanches et al., 2016; Santos et al., 2007), suggests that classical
psychedelics and ketamine might share a related therapeutic
mechanism.
Although the molecular targets of ketamine and psychedelics
are different (NMDA and 5-HT2A receptors, respectively), they
appear to cause similar downstream effects on structural plasticity
by activating mTOR. This finding is significant because ketamine is
known to be addictive whereas many classical psychedelics are
not (Nutt et al., 2007, 2010). The exact mechanisms by which these
compounds stimulate mTOR is still not entirely understood, but
our data suggest that, at least for classical psychedelics, TrkB
and 5-HT2A receptors are involved. Although most classical psychedelics
are not considered to be addictive, there are still significant
safety concerns with their use in medicine because they
cause profound perceptual disturbances and still have the potential
to be abused. Therefore, the identification of non-hallucinogenic
analogs capable of promoting plasticity in the PFC could
facilitate a paradigm shift in our approach to treating neuropsychiatric
diseases. Moreover, such compounds could be critical to
resolving the long-standing debate in the field concerning whether
the subjective effects of psychedelics are necessary for their therapeutic
effects (Majic et al., 2015  ). Although our group is actively
investigating the psychoplastogenic properties of non-hallucinogenic
analogs of psychedelics, others have reported the therapeutic
potential of safer structural and functional analogs of ketamine
(Moskal et al., 2017; Yang et al., 2015; Zanos et al., 2016).
Our data demonstrate that classical psychedelics from several
distinct chemical classes are capable of robustly promoting the
growth of both neurites and dendritic spines in vitro, in vivo, and across species. Importantly, our studies highlight the similarities
between the effects of ketamine and those of classical serotonergic
psychedelics, supporting the hypothesis that the clinical
antidepressant and anxiolytic effects of these molecules might
result from their ability to promote structural and functional plasticity
in prefrontal cortical neurons. We have demonstrated that
the plasticity-promoting properties of psychedelics require
TrkB, mTOR, and 5-HT2A signaling, suggesting that these key
signaling hubs may serve as potential targets for the development
of psychoplastogens, fast-acting antidepressants, and anxiolytics.
Taken together, our results suggest that psychedelics
may be used as lead structures to identify next-generation neurotherapeutics
with improved efficacy and safety profiles.

Also below is a great article on DMT and neuroplasticity:

 

Dark Classics in Chemical Neuroscience N,N-Dimethyltryptamine DMT

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Ketamine Consultants Blog

Ketamine is a dissociative anesthetic that acts on the central nervous system by antagonizing the n-methyl-d-aspartate (NMDA) receptors. It is a rapid acting anti-depressant, but there is a lot more attention being paid to it’s efficacy in alcohol and drug abuse treatment.

Ketamine has been shown in some studies to prolong abstinence from alcohol and drug use disorders. It also has been found to reduce cocaine craving and self-administration in untreated patients.

The mechanisms by which this works has been through the disruption of relevant neural networks which blocks reconciliation of drug-related memories, neuroplasticity and neurogenesis, and enhancing psychological therapy.

We know that addiction is a chronic relapsing disorder with cravings, drug seeking, and unpleasant withdrawal symptoms upon cessation of the drug. Relapse rates with current therapies are between 40-80%.

Pre-clinical research on Ketamine has shown effectiveness in alcohol intake in a rat model:

Alcohol-preferring rats could self-administer
0.08% weight/volume saccharin, 10% weight/volume ethanol or
water. After intraperitoneal administration of either ketamine or
memantine, operant responding and motor activity were assessed.
A dose of 20 mg/kg of ketamine reduced ethanol administration
significantly (33.3% less than vehicle-treated rats) without affecting
motor activity and water consumption. Importantly, coadministration
of rapamycin blocked ketamine-mediated reduction
of alcohol intake, but not that of memantine (Sabino et al.,
2013). Similarly, ketamine’s antidepressant effects are suppressed
by rapamycin. mTOR activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats

Also:

Both ketamine and NBQX attenuate alcohol drinking in male Wistar rats.

The devastating consequences of alcohol-use disorder (AUD) on the individual and the society are well established. Current treatments of AUD encompass various strategies, all of which have only modest effectiveness. Hence, there is a critical need to develop more efficacious therapies. Recently, specific glutamatergic receptors have been identified as potential novel targets for intervention in AUD. Thus, the current study was designed to evaluate the effects of acute administration of sub-anesthetic doses of ketamine, an NMDA receptor antagonist, as well as NBQX, an AMPA/kainate receptor antagonist on alcohol intake and its possible behavioural consequences. Adult male Wistar rats were trained in drinking in dark paradigm (3 weeks), and following stable alcohol intake, ketamine, NBQX as well as their combination were injected prior to a 90 min drinking session. In addition to alcohol intake, sucrose preference (overnight), and locomotor activity and forced swim test (FST) were also evaluated before and following alcohol intake. Both doses of ketamine (5 and 10 mg/kg) and NBQX (5 and 10 mg/kg) significantly attenuated percent alcohol intake. The combination of the higher dose of ketamine and NBQX, however, did not significantly affect percent alcohol intake. Moreover, animals exposed to alcohol showed decreased sucrose intake (reflective of anhedonia), decreased locomotor activity and swimming in the FST (reflective of helplessness), that were not affected by ketamine and/or NBQX. These results suggest that selective antagonism of the NMDA or AMPA/kainate receptors may be of therapeutic potential in AUD.

Addiction is characterised by disruptions in learning and memory. Addicts develop cue-specific responses to drug-related
cues. One preclinical study examined the effects of ketamine administration on reconsolidation
where memories are rendered more labile following reactivation. After morphine CPP ( conditioned place preference) was induced, rats were intraperitoneally administered 60 mg/kg of ketamine after being reexposed to the conditioned context or while they were in their home cages. After ketamine administration, preference for morphine decreased significantly in the first retest.  This has been interpreted as evidence that ketamine successfully disrupted reconsolidation of the environment-drug memory.

Effects of scopolamine and ketamine on reconsolidation of morphine conditioned place preference in rats

Persistent memory associated with addictive drugs contributes to the relapse of drug abuse. The current study was conducted to examine the effects of scopolamine and ketamine on reconsolidation of morphine-induced conditioned place preference (CPP). In experiment 1, after morphine CPP was acquired, rats were injected with ketamine (60 mg/kg, intraperitoneally) and scopolamine (2 mg/kg, intraperitoneally), respectively, after reexposure to an earlier morphine-paired context or in their home cages. The CPP was reassessed 24 and 48 h after reexposure. An additional group of rats received saline following reexposure to the earlier morphine-paired context. In experiment 2, two groups of rats were only given saline during the CPP training and subsequent administration of ketamine or scopolamine during the reexposure. In experiment 1, rats failed to exhibit morphine CPP when ketamine and scopolamine were administered only after reexposure to a morphine-paired context. CPP was not abolished by ketamine or scopolamine administration in the animals’ home cages. Also, the animals receiving only saline injections showed strong morphine CPP 24 h after a short exposure to the morphine-paired context. In experiment 2, ketamine or scopolamine treatment alone did not induce CPP or aversion. Administration of scopolamine and ketamine, after reexposure to a drug-paired context, resulted in the disruption of morphine CPP, suggesting the potential effects of scopolamine and ketamine in disrupting memory associated with environmental cues and addictive drugs.

The capacity of ketamine to treat addiction was not investigated scientifically until decades later when Krupitsky and
Grinenko (1997), published work that reported the use of ketamineto reduce relapse in recently detoxified alcoholics. These
published results were a review of 10 years of previous research.The procedure that was investigated was referred to as Ketamine Psychedelic Therapy (KPT) and had been applied since the mid-80sin the former Soviet Union, until ketamine was banned in Russia 1998.  Ten Year Study of Ketamine Psychedelic Therapy (KPT) of Alcohol Dependence [

KPT consisted of three stages. The first step was the preparation,during which patients underwent a preliminary psychotherapy session where a psychotherapist discussed with them the content of the psychedelic experience. They were told that under the influence of ketamine, they would view the world symbolically, realise about the negative aspects of alcohol dependence and see the positive sides of sobriety. They were also told that they would become aware of unconscious mental concepts about the negative aspects of their addiction, such as their personal problems and their self-identity. These insights would help them to accept new life values, purposes and meaning of life and in turn e to overcome
their alcoholism. The second stage was the ketamine session in which ketamine was intramuscularly injected and the psychotherapist interacted with the patient. The psychotherapist verbally guided the patient, with the aim of creating new meaning and purpose in life. At moments of highly intense psychedelic experience, the smell of alcohol was introduced to the individuals. The idea was to enhance the negative emotional valence of the thoughts related to alcohol during the session. Finally, group psychotherapy was performed after the session. The aim of this session was to help patients integrate
insights of psychedelic experience into their lives. It is reported that this procedure was used in
over 1000 alcoholics with no reported complications.In Krupitsky and Grinenko, 1997 report, relapse rates in a group
of recently detoxified alcohol dependent patients undergoing KPT (n ¼ 111) were compared with another group of alcohol dependent patients who were treated with treatment as usual (n ¼ 100). Both groups underwent alcohol detoxification before treatment. After these sessions, the KPT group received an intramuscular injection of ketamine (2.5 mg/kg) along with the corresponding preparation. The control group received ‘conventional, standard methods of treatment’ in the same hospital. Only 24% of the control group remained abstinent after a year, whereas 66% of the KPT group did not relapse during the same period (p < .01).

In a further study, 70 detoxified heroin-dependent patients were randomised into two KPT groups, who were injected different doses of ketamine, in a double-blind manner (Krupitsky et al., 2002). One group (n ¼ 35) received 0.2 mg/kg i.m. of ketamine, which was considered an active placebo, whereas the experimental group (n ¼ 35) received 2.0 mg/kg i.m. After two years, the higher dose of ketamine resulted in a greater rate of abstinence (17% vs 2% abstinent subjects, p < .05). Additionally, the experimental group had a larger positive change in nonverbal unconscious emotional attitudes and a greater and longer-lasting reduction in craving for heroin. The authors therefore concluded that effectiveness of ketamine
was dose dependent. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up

In 2007, Krupitsky’s lab compared the impact of a single vs three KPT sessions (dose: 2.0 mg/kg, i.m.) (Krupitsky et al., 2007). Fifty nine detoxified heroin dependent patients first received a KPT session. After this, 6 participants relapsed and abandoned the treatment. The remaining participants were randomised into two groups: one received a further two KPT sessions (n ¼ 26) in monthly intervals, whereas the other underwent two counseling sessions (n ¼ 27) also in monthly intervals. After a year, 50% in the 3-session KPT group remained abstinent compared to 22% in the single KPT (p < .05) (Krupitsky et al., 2007). This clearly demonstrates the superior efficacy of three KPT sessions in comparison to
one KPT session, which indicates that the KPT sessions are beneficial.  Single Versus Repeated Sessions of Ketamine-Assisted Psychotherapy for People with Heroin Dependence 

In a private psychiatric practice in the US, another psychiatrist has successfully conducted KPT since 1994. He has not only treated patients with drug addiction, but also individuals with other types of addictions (e.g. food addiction) and other psychological disorders. His reported anecdotal, clinical findings are positive, having adhered strictly to the original protocol.  Ketamine Enhanced Psychotherapy: Preliminary Clinical Observations on Its Effectiveness in Treating Alcoholism. Kolp, Eli,Friedman, Harris L.,Young, M. Scott,Krupitsky, Evgeny The Humanistic Psychologist, Vol 34(4), 2006, 399-422

Abstract:

Ketamine is a dissociative anesthetic widely used by physicians in the United States and also a psychedelic drug that physicians can legally prescribe off-label within the United States for other therapeutic purposes. It has been used in Russia and elsewhere to successfully treat alcoholism and other psychological or psychiatric problems, but has not been researched for this purpose in the United States. Results of a series of clinical trials using ketamine for treating alcoholism in the United States are retrospectively reported, along with 2 case studies of how psychotherapy facilitated by this substance helped two individuals achieve abstinence through ketamine’s transpersonal effects. Considering the massive problems caused by alcoholism, the need to begin formal research studies on ketamine psychotherapy for alcoholism is emphasized.

In 2014, 8 cocaine dependent males disinterested in treatment received 3 infusions in a double-blind, cross-over design: 0.41 mg/ kg ketamine, 0.71 mg/kg ketamine, and 2 mg lorazepam (an active benzodiazepine control, which induces mild subjective and anxiolytic effects) (Dakwar et al., 2014b). Infusions lasted 52 min and were separated by 48 h. Before and after each infusion, motivation to quit cocaine and cue-induced craving were assessed. Relative to the lorazepam, motivation to quit cocaine was enhanced and cueinduced craving for cocaine was reduced by the 0.4 mg/kg ketamine (both ps ¼ 0.012), and this latter effect was augmented by the 0.71 mg/kg ketamine dose. During the psychedelic experience,
dissociation and mystical-type effects were assessed. As predicted, the higher dose of ketamine led to greater mystical experiences. Strikingly, these mystical-type experiences, but not the dissociative effects, were found to mediate motivation to quit. However, the small non-treatment-seeking sample, the absence of an inactive placebo and the cross-over design, limit the results.Having said that, the participants showed a significant reduction in the frequency and amount of cocaine
consumed in normal life in the 4 weeks following the experiment, compared to baseline. Dakwar, E., Levin, F., Foltin, R.W., Nunes, E.V., Hart, C.L., 2014b. The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers. Biol. Psychiatry 76, 40e46. https://doi. org/10.1016/j.biopsych.2013.08.009.

Also, more cocaine research from the same group is here:

Cocaine self-administration disrupted by the N-methyl-D-aspartate receptor antagonist ketamine: a randomized, crossover trial E DakwarMolecular Psychiatry volume22pages76–81 (2017) |

Abstract:

Repeated drug consumption may progress to problematic use by triggering neuroplastic adaptations that attenuate sensitivity to natural rewards while increasing reactivity to craving and drug cues. Converging evidence suggests a single sub-anesthetic dose of the N-methyl-D-aspartate receptor antagonist ketamine may work to correct these neuroadaptations and restore motivation for non-drug rewards. Using an established laboratory model aimed at evaluating behavioral shifts in the salience of cocaine now vs money later, we found that ketamine, as compared to the control, significantly decreased cocaine self-administration by 67% relative to baseline at greater than 24 h post-infusion, the most robust reduction observed to date in human cocaine users and the first to involve mechanisms other than stimulant or dopamine agonist effects. These findings signal new directions in medication development for substance use disorders.

Neural plasticity is defined as the cellular and structural reorganisation
of the brain. Synaptogenesis is a crucial mechanism for
plasticity, since for change to happen within brain circuitry new
synapses between neurons must be formed. Surface expression of
AMPARs and upregulation of other synaptic proteins are involved in
the process of synaptogenesis. Diminished glutamatergic synaptic
transmission and reduced plasticity are thought to be associated
with addiction. Existing models suggest that ketamine’s blockade of NMDA receptors
increases synaptogenesis by stimulating protein synthesis
and the insertion of AMPA receptors. Hence, ketamine’s
effects help to reverse the glutamatergic changes associated
with depression and addiction. 

Animal models of addiction, depression and other psychiatric disorders
have been linked to a reduction in adult neurogenesis . It has been suggested that in addiction
the loss of neurogenesis, especially in cortical and hippocampal
regions, may contribute to levels of self-administration and the
vulnerability of relapsing. The reduction of neurogenesis in addiction is supported in
humans by the reduction in BDNF serum levels. In a study, 37
subjects with diagnosis of alcohol dependence showed significantly
reduced BDNF serum levels compared to healthy individuals
. Similarly, cocaine- and heroin-dependentpatients have significantly lower serum BDNF levels and these
seem to recover during withdrawal. Rapid and transient up-regulation of the neuroplasticity marker
BDNF is implicated as a critical component of the antidepressant
mechanism of ketamine . BDNF knock-out mice do not show anti-depressant response to
ketamine in animal models of depression.

Recent research has
demonstrated that ketamine increases peripheral plasma BDNF in
depressed people who respond to treatment but not in treatment
non-responders or patients receiving an active placebo. These BDNF increases in depressed people given ketamine
are robustly correlated with the drug’s antidepressant effects.

It has been found there is a dispersion in normal brain connectivity and the disruption of the usual pattern of communication  in depression and addictions. . The integrity of functional networks decreased, being the
change maximal in functional hubs such as the thalamus, putamen
and high-level association cortices. In particular, connectivity
within the Default Mode Network was reduced between the posterior
cingulate cortex and the mPFC .
The connectivity between the parahippocampal and the retrosplenial
cortex also decreased as well as the segregation between
other major functional networks such as the salience, attention and
different visual networks Infusions of ketamine have shown to decrease connectivity
between and within resting-state consciousness networks.
Connectivity between the mPFC and the rest of the Default
Mode Network (via the posterior cingulate cortex) has been found
to be reduced, along with the integrity and activity of the salience
and visual networks are also affected. Since it is known
that connectivity with the mPFC is elevated in depression , the reduction of connectivity in the Default Mode
Network observed during the psychedelic experience might be a
mechanism that helps treat depressive states, which are very
common in addicts and predictive of relapse.

Given addiction is highly co-morbid with depression   and ketamine’s role within psychiatry changed
dramatically when it was discovered to be an anti-depressant, we
now briefly describe the research concerning ketamine and
depression. In 2000, the first clinical trial hinted at the potential of
ketamine as a treatment for depression. Four subjects diagnosed
with depression were intravenously administered 0.5 mg/kg of
ketamine in a randomised, double-blind design. The results were
compared to the injection of saline solutions in 3 subjects with an
equivalent diagnosis. Comparison on the Hamilton Rating Scale for
Depression (HAM-D) showed moderate evidence for a greater
reduction in scores after ketamine infusion compared to saline
(Berman et al., 2000). The reduction was rapid and outlasted the
subjective effects of ketamine, lasting for 3 days after infusion.
Despite the small sample size and the limited follow-up, this result
and anti-depressant effects observed in animal models of depression
encouraged researchers in the field to perform more studies in humans . Since then, over 30 studies have
examined the antidepressants effects of ketamine in patients with
treatment-resistant major depressive and bipolar disorders.

Ketamine has shown a 65-70% response rate in treating
depression within 24 h, which contrasts with the ~47% response
rate of conventional monoaminergic antidepressants after weeks
or months . Furthermore,
ketamine’s antidepressant actions are almost immediate and last
for approximately a week ,
whereas conventional antidepressive medications take weeks to
have an effect, are given daily and most of them fail to exert long lasting
effects . Furthermore, studies
have consistently shown that after a ketamine infusion there is a
significant reduction in suicidal ideation which also lasts for several
days.Depression and addiction’s co-expression is almost ubiquitous
People with alcohol, opioids, cannabis and
cocaine use disorders show notably higher rates of depression than
the average of the general population. Furthermore, high levels of depression and anxiety
may predispose relapse to: heroin, alcohol, cannabis and cocaine.

Memories and their creation and alteration is felt to be at the heart of cues and triggers and relapse in addiction. Once consolidated, memories are thought to be stored in a
stabilised state after initial acquisition. Shortly after reactivation
(i.e. remembered) of consolidated memories, these are rendered
transiently unstable and labile, before they then re-stabilise. This
process has been named reconsolidation . After reconsolidation,
the memories are stored again, but they may have been slightly
altered or updated. Each time memories are reactivated the latest
version is retrieved and they are again susceptible to change. During reconsolidation memories may be vulnerable to
manipulation and disruption. This was first demonstrated in animals
using fear conditioning. Rodents were trained to associate a
neutral stimulus with a shock such that the neutral stimulus elicited
a fear response. Researchers eliminated this fear response by
pharmacologically disrupting the reconsolidation process . Reward memories can also be disrupted such that a
neutral stimulus that once elicited appetitive behaviour no longer
does so. Therefore, non-pharmacological and drug therapies that
aim at weakening drug-cue memories via manipulation of reconsolidation
are of interest. Preclinical studies have shown that ketamine affects reconsolidation
of drug memories. . A recent review has suggested that ketamine (along with other psychedelics)
may be able to disrupt maladaptive appetitive memories
(Fattore et al., 2017).  Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine

Article ABSTRACT:

Rationale

Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial “psychedelic effect,” which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy.

Objective

Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories.

Results

We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition.

Furthermore, a meta-analysis of pre-clinical
studies found evidence suggesting that NMDAR antagonists can
be used to target reward memory reconsolidation, and more successfully
than adrenergic antagonists such as propranolol (Das
et al., 2013)  Das, R.K., Freeman, T.P., Kamboj, S.K., 2013. The effects of N-methyl d-aspartate and B-adrenergic receptor antagonists on the reconsolidation of reward memory: a meta-analysis. Neurosci. Biobehav. Rev. 37, 240-255.:

Abstract

Pharmacological memory reconsolidation blockade provides a potential mechanism for ameliorating the maladaptive reward memories underlying relapse in addiction. Two of the most promising classes of drug that interfere with reconsolidation and have translational potential for human use are N-methyl-d-aspartate receptor (NMDAR) and B-Adrenergic receptor (B-AR) antagonists. We used meta-analysis and meta-regression to assess the effects of these drugs on the reconsolidation of reward memory in preclinical models of addiction. Pharmacokinetic, mnemonic and methodological factors were assessed for their moderating impact on effect sizes. An analysis of 52 independent effect sizes (NMDAR = 30, B-AR = 22) found robust effects of both classes of drug on memory reconsolidation, but a far greater overall effect of NMDAR antagonism than B-AR antagonism. Significant moderating effects of drug dose, relapse process and primary reinforcer were found. The findings suggest that reward memory reconsolidation can be robustly targeted by NMDAR antagonists and to a lesser extent, by B-AR antagonists. Implications for future clinical work are discussed.

Highlights

► Meta-analysis of NMDAR and B-adrenergic antagonists in preclinical reward reconsolidation. ► Larger effects of NMDAR (r = .613) than B-adrenergic (r = .24) antagonists were found. ► ‘Relapse process’, trace type, reinforcer and drug dose moderated effect sizes. ► NMDAR antagonists particularly might be of clinical use in treating addiction.

 

.

                                                           Mystical experiences and psychedelic effects

Mystical experiences and psychedelic effects provoked by
classic psychedelic drugs have been shown to be psychologically
beneficial in long-term studies.They have not only been linked with positive
outcomes in various treatments, but also to ‘life-changing’,
‘spiritually meaningful’ and ‘eye opening’ events.In the ketamine studies described
above, anecdotal and qualitative reports suggest that the subjective
psychedelic experience seemed to help patients. For example, to
help them: undergo a cathartic process, improve relationships with
the world and other people, maintain positive psychological
changes and enhance self-awareness and personal growth.During KPT, patients reported a feeling of ‘resolution’ and
‘catharsis’ of some psychological problems, mainly those related to
alcohol. Furthermore, the degree of mystical experience was also
linked to the insight and impact of KPT reported by patients
. Interestingly, the intensity of the negative experiences (experiences associated
with negative emotions, fear and horror) during the
ketamine session was associated with longer remission. This was
blindly and quantitatively assessed by analysing patient’s selfreports.
Moreover, spirituality, self-concept, emotional attitudes
to other people and positive changes in life values and purposes
were improved after the ketamine experience.

Notably, ketamine’s mystical experiences, but not dissociative
effects, were found to mediate ketamine’s increase motivation to
quit 24 h after the infusion in cocaine addicts .
Moreover, consistent with previous studies, it was also observed
that mystical experiences were positively dose-dependent. This
study therefore provides evidence that the mystical experience
induced by ketamine is important in its therapeutic mechanism
. Speculatively, mystical experiences may help
to rapidly shift patients’ mindsets towards the integration and
acceptance of a sober lifestyle.

The acute disruptions of the functional networks, especially the
alterations to the default mode network, are related to the psychedelic
experience. In fact, the degree of network dissolution in
LSD and psilocybin is correlated with the intensity of the psychedelic
experience . The disruption to the default mode network may engender a reduction
in rumination and maladaptive repetitive thoughts. Psychological
therapies for addiction often aim to help the patient consider
different ways of life, especially those without the drug, and a
pharmacological agent such as ketamine which expedites that
process may be useful in treating addiction.

Speculatively, ketamine can
provide a unique mental state during and after acute drug effects
that facilitates and enriches therapeutic experiences, which in turn
may improve efficacy and lengthen treatment effects. Furthermore, synaptogenesis
and neurogenesis are putatively critical in learning new
information . The uptake of psychological therapy may
therefore be facilitated after ketamine infusions due increases in
synaptogenesis and neurogenesis, and thus improved learning of
relapse-reducing strategies, such as those used in relapseprevention
based cognitive behavioural therapy (CBT). In fact, the
idea that neurogenesis and synaptogenesis work synergistically
with psychological therapies is becoming recognised as a new
approach in the treatment of mental disorders . Theoretically, the administration of ketamine (which can
produce a ‘psychedelic’ experience) may open people’s minds so
they are more able to embrace what is presented during therapy as
well as enhancing the uptake of new therapeutic content.

The promise of ketamine in the treatment of addiction is supported
by research with large treatment effect sizes, especially in
comparison to existing treatments. In recently detoxified alcoholics,
ketamine treatment increased one-year abstinence rates in
alcoholics from 24% in the control to 66% in the ketamine group
(Krupitsky and Grinenko, 1997) and reduced cocaine self administration
by 67% relative to baseline in non-treatment
seeking cocaine users (Dakwar et al., 2016). These results clearly
demonstrate profound effects of ketamine administration (with
and without therapy) on drug and alcohol use, of an order of
magnitude which is 2 or 3 times more effective than existing
pharmacotherapies.

Ketamine for the treatment of addiction Evidence and potential mechanisms

 

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Prolon Fasting Mimicking Diet | Weight Loss Fairfax, Va | 703-844-0184

ProLon – Fasting Mimicking Diet

For many of us looking to achieve a healthier and leaner body, dieting is one of the crucial components in a comprehensive body makeover regimen in addition to exercise and regular check-ups. However, with the explosion in new diet regimens, which one to choose? Let’s dive in and explore one of the hottest new diets on the scene that is gaining popularity: The fasting-mimicking diet (FMD).

ProLon is an exciting new diet rooted in science with an emphasis on longevity. If you’re looking long-term to improve your overall longevity and healthy aging in addition to losing or maintaining healthy weight in a safe and scientifically-proven manner, Dr Valter D. Longo’s fasting-mimicking diet may be the right option for you.

The ProLon FMD was conceived by Dr Longo at the University of Southern California. As a director of the USC’S Longevity Institute, he devotes his career to finding new ways to extend healthy lifespan. It was with this background and experience that he devised ProLon. The meat-free 5-day diet was studied at USC in both humans and animals, allowing Dr Longo to refine and improve the diet for optimal results.

As the name suggests, the fasting-mimicking diet (FMD) is intended to simulate the effects of a fast over five days without the downsides. This allows for the improved healthy benefits of doing intermittent fasting without having to constantly fast!

What are some of those benefits as seen in all the studies? They include decreased blood sugars and risk of diabetes, improved diabetes markers, decreased body inflammation, decreased risk of certain cancers, lower cholesterol levels, and a very powerful benefit noted in all studies was the specific decrease of visceral belly fat. Visceral belly fat is the fat that increases the risk for major metabolic diseases in the body. You lose it! Despite consuming food during the 5 day diet, your body will be tricked into thinking it’s not eating, forcing it to go into a fasting mode. This is a diet that can be followed for 5 days yet reap the benefits of a lifetime of intermittent fasting!

In order to ensure you get the right amount of nutrients, ProLon comes in the form of pre-packaged and pre-produced meal kits rich in fatty acids and low in carbs and protein. Unlike the other fasting diets, you only need to do ProLon five days each month! That may not seem like much, but studies have found that it increased healthspan in mice by 11% and improved health metrics in human trials. You can lose weight while maintaining a lean body mass, improve your energy levels, and enjoy healthier skin overall. Studies have shown ProLon can help slow down the effects of ageing, prevent cardiovascular disease and Alzheimers, as well as preventing diabetes.

If you are already at your goal or ideal weight you can do the FMD every other month or every 3 to 4 months. Used that way, ProLon actually helps you not only maintain that weight but continue to improve on your metabolic health markers and decrease your visceral fat as noted earlier! There are some conditions when doing the fast: you should not do exercise as you temporarily decrease energy intake for the five days. Also, there are some minor side effects associated with a lower caloric intake such as fatigue or headaches. It’s not recommended to do the fast more than once a month, as prolonged fasting without a break can cause negative effects.

If you’re looking to reduce your weight, maintain a healthy weight, decrease your chances for developing cancer or other diseases, come visit us at NOVA Health Recovery where we can help you go over your nutrition and wellness options. We give you a report that outlines your metabolic priorities and gives you a plan for improvement and maintenance. We are knowledgeable in and provide a wide range of weight loss and metabolic improvement programs in addition to ProLon. Remember, it is NOT about giving the same program to everyone, rather, take into consideration the individual issues and needs. We can help you decide what works best for you as part of an individualized comprehensive metabolic improvement plan.

A Good Fast is better than a Bad Meal”  ~ Old Irish Proverb

“He who eats until he is Sick must Fast until he is Well.”  ~ Old English Proverb

Over the decades doctors and nutritionists have been solely focused on what to eat for health and weight loss. More recently, scientists have recognized that we should also be concerned about WHEN we should be eating as part of our dietary approach to overall health and wellness.

For centuries, fasting has been a large part of religious experiences including all factions of the Christian, Jewish, Buddhist, Hindu, and Muslim faiths. Religious fasting has various intentions including bringing oneself closer to God or self awareness, to physically and spiritually purify oneself, and to become closer to an understanding of world suffering and solutions.  An example of a modern day religious approach to fasting is exemplified by the Church of Jesus Christ of Latter Day Saints where members fast for 24 hours on the first Sunday of each month. Members are encouraged to donate the money usually used for food towards benefitting those less fortunate. The common denominator for religious fasting is purposeful giving and mindfulness for the improvement of an individual’s health and overall wellness.

In the late 19th century, Dr. Edward H. Dewey, a famous Civil War Surgeon and U.S. Assistant Surgeon General, wrote a series of books and articles on intermittent fasting for health and the improvement of multiple social ills. More recently, scientists have looked closer to intermittent fasting as a powerful tool for weight loss and longevity.

What is the definition of fasting? It turns out there is no single definition in the scientific literature. However, there are 3 common approaches:

  1. Meal skipping for a 24 hour period
  2. Alternate Day fasting where you eat approximately 400 to 600 calories total for one day then eating as you would normally the following day and repeating this pattern.
  3. Timed restricted feeding where you eat as you normally would during an 8 hour period then fasting during the remaining 16 hours.

Each of these has different variations to the base and all have been shown to have some sort of physiologic benefit. Intermittent fasting has gained a lot of attention in obesity and “anti-aging” research. Two key questions need to be answered:

  1. Does it really work for weight loss and longevity?
  2. Is intermittent fasting safe?

It turns out there is good literature support on both the safety of fasting and the positive effects on health. Both animal and human studies have supported intermittent fasting for weight loss, the maintenance of healthy weight, improvements in blood pressure, blood sugar, and the slowing of the aging process overall.  Dr Volter Longo, the Director of the University of Southern California Longevity Institute published a human study earlier this year showing that a 5 day modified intermittent fasting diet done once a month for 3 months helped individuals lose body fat, waist size and weight, improve BMI and overall laboratory health markers without adverse side effects. Dr. Longo admits there is a need for more studies but says this approach to intermittent fasting has the best promise for improved overall health, quality of life, and healthy longevity.

Intermittent fasting has been shown to increase your body’s ability to produce more growth hormone naturally, improve insulin sensitivity thus allowing your body to access fat storage more readily, allow for cellular repair by breaking down old cells and building new ones, and help turn off the genes that cause aging, and keep the youth genes going longer.

These are my general guidelines and overall recommendations:

First, NEVER begin a fasting diet without proper physician advice.

Visit a Center that specializes in Dietary approaches, such as NOVA Health Recovery.

Fasting is easier than you think. Remember, over 1/3rd of the world’s population voluntarily fasts safely. Fasting needs to be purposeful in order to be effective. Fasting Mimicking Diets can be powerful tools for improved health and longevity. Proper monitoring with baseline labs and biometric measurements by your doctor can ensure you reach your goals and long term success.

Cell-Metabolism-on-Fasting-Molecular-Mechanisms-and-Clinical-Applications
Fasting-mimicking diet and markers risk factors for aging, diabetes cancer and cardiovascular diseases
Cell-Metabolism-Low-Protein-Intake-Is-Associated-with-a-Major-Reduction-in-Overall-Mortality
Association of Animal and Plant Protein Intake with all cause and cause specific mortality
Enhancing Stem Cell Transplantation
Can a Diet That Mimics Fasting Turn Back the Clock

Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras PKA, Tor, and Sch9

Critical Role of Zinc as Either an Antioxidant or a Prooxidant in Cellular Systems.

Proteostasis, oxidative stress and aging.

Protein Turnover in Aging and Longevity

Promoting Health and Longevity through Diet from Model Organisms to Humans

Dietary Restriction, Growth Factors and Aging from yeast to humans

Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys

Aging and Caloric Restriction Research A Biological Perspective With Translational Potential

Dietary restriction with and without caloric restriction for healthy aging

Impact of caloric restriction on health and survival in rhesus monkeys the NIA study

Calorie restriction as an intervention in ageing v

Calorie restriction as an intervention in ageing

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Role of dietary amino acid balance in diet restriction‐mediated lifespan extension, renoprotection, and muscle weakness in aged mice

nterventions to Slow Aging in Humans Are We Ready

Maillard Proteomics Opening New Pages

Protein carbamylation is a hallmark of aging.

Protein Carbamylation A Marker Reflecting Increased Age-Related Cell Oxidation.

Identification of HSP90 inhibitors as a novel class of senolytics

Pharmacological Strategies to Retard Cardiovascular Aging

Cyclic AMP Mimics the Anti-ageing Effects of Calorie Restriction by Up-Regulating Sirtuin

Sirtuins as Mediator of the Anti-Ageing Effects of Calorie Restriction in Skeletal and Cardiac Muscle

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan.

Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys

___________________________________________________

Fasting Mimicking diets (FMD):

  • Turns off pro-aging genes such as IGF-1, TOR, and PKA
  • We go into a shielded mode and activate reparative enzymes when we fast
  • During fasting, we destroy damaged intracellular organelles and activate stem cells which rejuvenates tissues

In Humans, a monthly 5 day cycle of FMD done three months does the following:

  • Rejuvinates the immune system
  • decreases cancer risk
  • increases hippocampal neurogeesis
  • increases cognitive performance
  • Decreases age related diseases

Stem cells get worse with age and FMD will improve tissue maintenance and decrease carcinogenesis. FMD Reverses aging in mesenchymal stem cells by 45 times and there is an 800% increase in proliferation of stem cells.

IGF1 and PKA inhibits stem cells from regenerating, but fasting will prevent that and allows stem cells to grow.

As we age, disease risk goes up, and with diet, toxins, time – the disease risk goes up. But a FMD decreases the chances of diseases of aging , such as diabetes, Alzheimers, Strokes, and cancer.

FMD will reverse the effects of aging on white blood countif started in middle age. This allows for improved immune function, nerve regrowth, and improved cognition.

Also noted are improved biomarkers of humans for cardiovascular disease, cance, and aging.

FMD promotes rejuvenation.

5 days of a month, you do the FMD protocol for three months in a row without restrictions the other days.

Result of the FMD are:

  • Body weight loss (5 lb)
  • Decreased abdominal fay
  • Decreased waist circumference
  • Lean body mass maintained
  • IGF-1 decreases, Decreased systolic and diastolic blood pressure.
  • Decreased CRP and increased stem cells
  • Decreased cholesterol

If your BMI is >30 at the start, up to 9 lbs may be lost.

Most of the weight loss is visceral fat.

The body maintains the loss over time and protects the lean mass – Healing from within.

The significant benefits are maintained without other interventions:

  • Decreased BMI
  • Decreased weight circumferece
  • Lower Blood pressure
  • Decreased cholesterol
  • Maintains lean mass
  • Skin gets clearer and
  • Less joint pain

Impacted paramters for the better include:

  • Fasting blood sugar
  • CRP
  • Blood presusre
  • Cholesterol
  • Abdominal obesity

Protocol for FMD:

1100 calories day one then 77 cal/day days 2-5

  • Avoid exercise
  • avoid coffee
  • Nut- soy allergies – can’t use the program
  • Must be >18
  • Cannot be diabetic
  • Caffeine activates PKa so one cup is all you can use

About Fasting:

Abstinence from food switches us from utilizing sugars to utilizing fatty acids and ketones. Fasting has been utilized in religious contexts throughout the ages.

Fasting induces hormesis – a system strain that results in improvements.

Time restricted feeding  involvd eating over a period of 8 hours or less , i.e. 8 A.M – 4 P.M. as opposed to intermittent fasting with 16-48 hours of fasting with intervals of normal eating, such as the 5:2 diet. Periodic fasting lasts from 2-21 days.

 

Time restricted feeding results in: decreased weight, lower cholesterol, lower triglycerides, decreased inflammatory markers, lower glucose, and lower insulin, but UNKNOWN if it helps with rejuvenation!

For the intermittent fasting, such as 5:2 diet, i.e. 2 days/week of a 500 calorie diet, you get lower blood pressure, decreased abdominal fat and increased insulin sensitivity.

Periodic fasting (FMD) does the following:

  • extends lifespan
  • rejuvenates and regenrates
  • increases cognition
  • induces stress resistance

You get triglycerides, LDL , cholesterol, insulin sensitivity inprovemens

FMD involves using a specific macronutrient adjustment with protein restriction, mild calories restriction, and a low glycemic index. This results in lower Mtor/PKA/PKB and this promotes rejuvenation . It inhibits histone deacetylation.

SOD, Catalase, Nrf2 all up regulate due to the stress.

 

Prolon consists of:

  • Soups
  • BArs
  • Snacks
  • Tease
  • 66 ingredients
  • Glutein – dairy free

Prolon Review  << Link

Prolon diets result in increased mesenchymal stem cells in their blood – more regeneration

FMD compared to no intervention placed on a five day FMD for 5 days a month x 3 months, many changes occurred:

Lean body mass , cholesterol, CRP, Waist circumference, total body fat, Diastolic Blood pressure, LDL and total cholesterol all improved and lean body mass was maintained. the higher the BMI at the stare (BMI>30) had even more weight loss.

 

Results of the FMD :

  • Fat mass loss
  • preserves Lean muscle mass
  • stem cell rejuvination
  • Total fat loss

 

Glucose, IGF 1, blood pressure, BMI, waist circumference all remained improved after stopping following the FMD months later!

The source and amount of protein is important there is an increased rate of cancer and death increased by 3 times, but if plant based source of protein is used, then this does not occur.

Plant based protein source downregulates the IGF-1 and is good.

Tumor growth increases as we take in more protein in 50-65 year old group. This does not apply to ages>65

Lower amounts of a plant protein downregulated the IGF pathway for health.

higher intake of animal protein leads to higher mortality, but higher intake of plant protein is inversely associated with protein. Substitute 30% plant protein for meat protein was helpful.

Common fads such as juice fasting for weight loss and detox has LITTLE scientific evidence. It is not nutritionally adequate and needs careful planning. it is not a fast – it doesn’t suppress the same nutrient sensing pathway as FMD does.

How about the Ketogenic diet? High fat and low carb diet: It is nutritionally deficient – includes high cholesterol, high acid in blood , constipation, and micronutrient depletion (zinc, Vitamin D, selenium other)

The FMD promotes the following:

  1. Weigh loss
  2. Lean body mass protection
  3. Cholesterol imrpvement
  4. Improved fasting glucose
  5. Rejuvenation/regeneration

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. b

Protein Restriction, Epigenetic Diet, Intermittent Fasting as New Approaches for Preventing Age-associated Diseases

Can a Diet That Mimics Fasting Turn Back the Clock b

Prolon Clinical Review Webinar

 

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FMD in autoimmunity:

 

There may be a rational use for FM Din MS as well as it improves immunity:

A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms

Regulation of longevity by FGF21 Interaction between energy metabolism and stress responses

The JAMA Article for FMD is below:

Even though the results weren’t comparable with those in animal models, a few bright spots emerged. The second phase of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE 2) trial, which was funded by the National Institute on Aging (NIA) and the National Institute of Diabetes and Digestive and Kidney Diseases, demonstrated that it’s feasible for humans to limit calories for an extended period. In addition, participants who cut back on calories lost weight and kept it off for the duration of the study. There were no adverse effects on quality of life and the participants netted improvements in blood pressure, cholesterol, and insulin resistance—all risk factors of age-related diseases.

Scientists have known since the 1930s that restricting calories by roughly 20% to 50% without malnutrition dramatically extends the health span and life span of some strains of rodents, and in the decades that followed, caloric restriction has been shown to increase the healthy life span of creatures ranging from yeast to guppies to monkeys. It’s still an open-ended question whether dietary intervention—or any intervention at all—can dramatically extend humans’ maximum life span. But epidemiological evidence and cross-sectional observationsof centenarians and groups that voluntarily cut their calories strongly suggest that the practice could help people extend their average life span and live healthier, as well.

The problem is a practical one. If dieting is difficult, lifelong caloric restriction—which typically requires cutting 500 to 600 calories every day—may be unattainable for most people.

While participants in the CALERIE 2 trial did benefit from the intervention, they likely would have had better results had they achieved a full 25% reduction in calories, said Eric Ravussin, PhD, one of the study’s principal investigators and director of the Pennington Biomedical Nutrition Obesity Research Center at Louisiana State University.

“You can prescribe whatever you want, but it’s another story to have the people following that religiously,” he said.

Caloric Restriction Gets Real

Having come to terms with this reality, scientists have been seeking more practical approaches. They’ve increasingly become interested in fasting-based analogues to daily caloric restriction, such as time-restricted feeding, alternate-day fasting, intermittent fasting (1 fasting day or less alternated with 1 to 6 days of a normal diet), and periodic prolonged fasting (2 or more consecutive fasting days occurring periodically).

“We know fasting is sort of an acute version of calorie restriction,” said Eric Verdin, MD, a professor of medicine at the University of California, San Francisco, and president and chief executive officer of the Buck Institute for Research on Aging in Novato, California. Like caloric restriction, fasting—eating little to no food or caloric drinks over anywhere from 12 hours to a few weeks—has been shown to prevent disease and slow aging in a range of organisms.

In a 2011 NIA-cofunded study of young overweight women, a weekly fast—5 days of unrestricted eating and 2 consecutive days of 75% caloric restriction—produced outcomes similar to daily caloric restriction in reducing weight, total and low-density lipoprotein (LDL) cholesterol, and blood pressure, among other markers. The fasting plans used in this study and a follow-up spawned the “5:2” diets that have gained popularity in recent years.

The results of a recent phase 2 trial published earlier this year in Science Translational Medicine suggest that less severe energy restriction could provide bigger improvements with fewer fasting days per month. In the trial, dieters only had to restrict their calories 60% for 5 consecutive days a month over 3 months to get the benefits of the so-called fasting-mimicking diet.

The diet was developed by Valter Longo, PhD, a professor of gerontology and biological sciences at the University of Southern California and head of the Longevity Institute there. He has studied caloric restriction’s protective effects on aging and disease since the early 1990s.

Longo initially tested his diet in middle-aged mice, subjecting them to 4 consecutive days of the fast twice a month until their deaths. Mice on the diet lived an average of 11% longer than control mice—28.3 months vs 25.5 months—and had fewer cancers, less inflammation, less visceral fat, slower loss of bone density, and improved cognitive performance.

Autopsies revealed that fasting shrunk the rodents’ kidneys, hearts, and livers, but the refeeding period appeared to kick-start regeneration, increasing bone marrow–derived stem cells and progenitor cells and returning organs to normal weights.

In the same study, Longo also tested the diet in a small pilot clinical trial. After 3 monthly cycles of a 5-day fasting-mimicking diet, the 19 generally healthy participants in the intervention group reported no major adverse effects and had decreased risk factors and biomarkers for aging, diabetes, cardiovascular disease, and cancer compared with the control group, which maintained its normal caloric intake.

Those results were confirmed in Longo’s larger phase 2 trial reported this year, which enrolled 100 generally healthy participants. In the new study, the control group was crossed over to the dieting intervention after 3 months. In the end, 71 participants completed 3 consecutive cycles of the diet.

About a week after the end of the third cycle in the randomized arm of the study, the intervention group had lost an average of approximately 6 pounds while the control group had not lost weight. Dieters also had less trunk and total body fat, smaller waist circumference, and lower blood pressure and insulin-like growth factor 1 (IGF-1) levels compared with the control group. In the crossover arm of the study, the intervention had comparable effects.

The diet appears to help more those who need it the most, Longo said. Its effects on blood pressure and IGF-1 levels, as well as on body mass index and fasting glucose, triglycerides, total and LDL cholesterol, and C-reactive protein levels, were more pronounced among those who started the study with worse numbers. In fact, participants who entered the trial with prediabetes had fasting blood glucose levels in the normal range by the end of the intervention.

For researchers seeking to re-create the benefits of daily caloric restriction on a shorter, more practical timescale, Longo’s findings are tantalizing.

“I think that he’s definitely moving the ball forward,” said Rafael de Cabo, PhD, chief of the translational gerontology branch and the experimental gerontology section at the NIA.

Turning Back the Clock

Ravussin, who was not involved in the new study, said he suspects the participants’ weight loss led to the improvements. Although losing weight improves diabetes, Longo believes there’s more to the fasting-mimicking diet than shedding a few pounds, and it has to do with those organs that shrank and then regrew in his mouse study. “I think the regeneration and the rejuvenation is really at the center of this,” he said.

The idea holds water, according to de Cabo. “You take any animal that is older and you put them on caloric restriction, one of the first things that you observe is that any cell that is damaged tends to be turned over,” he said.

Longo recently published a mouse study in Cell that may begin to explain the process, at least in the pancreas. Six to 8 cycles of alternating a 4-day fasting-mimicking diet with a normal diet restored insulin-producing β cells and insulin secretion in diabetic mice, reducing their fasting blood glucose levels to almost normal levels. Increased expression of certain protein markers suggested that mice on the diet had greater numbers of pancreatic progenitor cells, which resulted in the generation of fully functional β cells.

Longo believes that postfasting stem cell activation drives the health and longevity benefits of his diet. “During the refeeding, the stem cells are turned on and … they rebuild the cells and systems and organs that have been reduced in size and cell number during the fasting,” he said.

The possibility of a nonsurgical, nonmedical therapy could be life changing for patients with diabetes.

“The implications are obviously incredible in the sense that by simply changing the diet you can regenerate β cells,” said Paolo Sassone-Corsi, PhD, director of the Center for Epigenetics and Metabolism at the University of California, Irvine. “It could be a revolutionary finding.”

Both Sassone-Corsi and de Cabo, who were not involved in Longo’s studies published this year, said they are testing the fasting-mimicking diet alongside other calorie-restricted diets in their laboratories to better understand the metabolic mechanisms behind their effects.

“To me the most important thing is we’re one step closer to understanding how we can translate the last hundred or something years of research on caloric restriction to actually get it to the clinic in an efficient way,” de Cabo said.

To that end, Verdin wants to see 2- or 3-year data from a larger diverse cohort, in part to learn the potential limitations of the diet. “You can imagine there could be a subset of people in which this diet will do a lot of good, and some others in which it will not do anything, and possibly in a small subset maybe do harm,” he said.

A Low-Cal Kit

The fasting-mimicking diet is commercially available as a 5-day meal plan. (Longo said he does not receive a salary or a consulting fee from the company that offers it and will donate 100% of his shares to charity.) The plant-based diet provides approximately 1100 calories on day 1 and around 750 calories on days 2 through 5. It’s low in proteins and carbohydrates and rich in healthful fats.

Despite the exciting findings in diabetic mice and humans with prediabetic markers, Longo cautioned that the meal plan isn’t ready for use in patients being treated for type 1 or type 2 diabetes because combining a fasting-mimicking diet with blood glucose–lowering drugs could cause hypoglycemia. He is working with diabetes experts to address safety concerns before launching a phase 3 multicenter trial involving patients with diabetes later this year. Temporarily stopping or reducing medications during the intervention could be a solution, he said.

Based on promising results in mouse models of multiple sclerosis and humans with the disease, Longo also wants to test the diet in patients with autoimmune disorders. Pending positive findings, he believes the fasting-mimicking diet could become the first food-based disease treatment to gain approval from the US Food and Drug Administration.

As with any diet, the question of adherence looms large—and assumptions may not turn out to be truths. Ravussin recently worked on a weight-loss study comparing alternate-day fasting with daily caloric restriction. Surprisingly, there was a higher percentage of dropouts in the fasting group.

But for now, the success of Longo’s pioneering studies is likely to trigger more trials of dietary interventions linked to caloric restriction. “This is just the beginning,” Verdin said.

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Old Club Drug Is Repurposed Into Depression Treatment

A North Texas woman said a popular club drug and animal tranquilizer saved her from a life of depression and suicidal thoughts.

You may have heard of the drug before, as Special K on the street. it was designed as a horse tranquilizer, but Ketamine is gaining popularity as a treatment for depression.

Some doctors believe the controversial drug will become a game-changer in slowing the nation’s suicide epidemic.

Tiffany McCombie, a 40-year-old mother of one, knows what depression feels like in its darkest moments.

“I definitely was feeling what I would consider suicidal, not really wanting to live, not really wanting to die, just numb. That’s not a healthy place for me,” McCombie said.

She said she has lived with depression and Bipolar disorder for 30 years, has tried dozens of medications and supplements to combat it, but nothing, she said, has worked as well as the Ketamine infusions she gets at Rise Wellness Center.

She’s had six of them in ten months.”I had the right attitude and wanted to be healed and believing that it was going to happen for me and my brain. It happened. It cut down the mood stabilizers and antidepressants I had been on for years. I don’t take them at all,” she said.

More studies,like this one, are finding that Ketamine may be more effective and work faster than traditional antidepressants.

A local team of anesthesiologists had used the drug before, as an anaesthetic inside the operating room, but after seeing its potential to treat depression, they opened Rise Wellness Center, which specializes in Ketamine infusions.

“We get people that are so far down and so dark that we need this to get them out, to get them up, to get them moving. No drug does that like Ketamine,” said Dr.  Renaud Rodrigue, a pain management physician at Rise Wellness Center.

Experts say Ketamine can be dangerous, even deadly, if abused or taken in large doses.

Even though it’s not FDA-approved to treat depression, Dr. Rodrigue said, when given in small doses and in a clinical setting, 90 percent of his patients with severe depression reported long-term benefits.

Researchers at the University of Illinois published this study about how Ketamine may trigger a depression-fighting protein in the brain.

“This protein changed the game for us. We know now there’s something that is created just by the drug itself, which is staying in the central nervous system and is exerting this affect way beyond the duration of the drug,” said Dr. Rodrigue.

McCombie said Ketamine saved her life.

Could Ketamine conquer Treatment resistant depression?

A notorious drug that can cause dangerous hallucinations and even death when abused may be the key to treating severely depressed patients when used under proper physician care. UT Southwestern’s Dr. Lisa Monteggia has uncovered how the drug Ketamine works so rapidly and why patients are seeing success when other treatments have failed.

Transcript

{Video opens with music and pictures of UTSW patient Megan Joyce along with her mother and with her husband.}

Megan Joyce: Everything in my life seems great.

Narrator: Megan Joyce’s life may look picture perfect.

Megan: I graduated college. I got married. He’s an amazing person. He is incredibly supportive.

Narrator: But what these happy photos hide is a relentless inner struggle.

Megan: This is not something that I love to admit, but I fight for my life every single day.

Narrator: The 27-year-old has spent more than a decade battling severe depression. It triggers for no obvious reason.

Megan: They have defined my bipolar illness as treatment resistant.

Narrator: She says she tried every medication in the books … as well as checking into inpatient and outpatient treatment centers. Nothing worked. Until doctors at UT Southwestern Medical Center tried something bold. Ketamine infusion therapy.

Megan: I don’t know if I would be here without the Ketamine treatment. I drive from Austin every 10 days, and I come for treatment, and I’m in the hospital for about 5 hours, and then I go home the same day.

Narrator: Several studies show ketamine can quickly stabilize severely depressed patients. But it does come with risks.

Dr. Madhukar Trivedi: There is a risk for addiction so that if people start taking Ketamine on their own on the black market, then that can be very dangerous. There are toxic effects in the brain if you overdose. On the other hand, for patients who do well on this and are getting the right dose under the guidance of a physician, it can be life saving.

Megan: When I have the IV in, it’s for 40 minutes, and then I stay for 2 hours after because it is an anesthetic so they want to make sure you don’t have adverse side effects.

Narrator: Dr. Madukhar Trivedi is closely monitoring Joyce … as well as the work his colleagues are doing at the bench.

Dr. Trivedi: At UT Southwestern, we have the whole breadth of work being done. There are people working like Dr. Monteggia in basic research. Understanding the exact mechanism of how Ketamine changes molecularly and changes the mechanism of action.

Dr. Lisa Monteggia: We got involved with how Ketamine triggers an anti-depressant effect because of the real need. Some of the recent clinical data has really shown that about a third of all patients don’t respond to anti-depressants. So, what do you do for treatment for those individuals?

Narrator: UT Southwestern’s Dr. Lisa Monteggia is a neuroscientist whose lab pinpointed a key protein that helps tigger Ketamine’s rapid antidepressent effects in the brain. Whereas traditional antidepressents can take up to 8 weeks to work, the effects of ketamine are seen within 60 to 90 minutes.

Dr. Monteggia: The idea of trying to understand how you generate a rapid anti-depressant response in patients … it’s really the first time we’ve been able to study it.

Narrator: Her study, published in the prestigious journal Nature, shows that ketamine blocks a protein responsible for a range of normal brain functions.

Dr. Monteggia: How we think Ketamine triggers an anti-depressant effect, this blocking the NMDA receptor, we think may also be causing the side effects associated with Ketamine. One of the things we’re working on is to try and see if we can identify compounds, slight derivatives perhaps, that may have the beneficial effects of Ketamine, in terms of triggering anti-depressant effects, without the side effects.

Narrator: In the meantime, Joyce remains optimistic for her future and the millions of others trying to defeat depression.

Megan: That’s why I really sought out Ketamine is I really wanted to give back and just have a chance at a semi-normal life.

Depression Patients Turning to Local Doctor’s Ketamine Therapy

The deaths of designer Kate Spade on Tuesday and TV Chef Anthony Bourdain Friday morning are bringing new attention to depression and suicide.

A new Center for Disease Control and Prevention report reveals suicide rates have risen 30 percent across much of the country since 1999.

But right here in San Diego, there is hope for a category of patients some doctors call “the untreatable.”

This patient, we’ll call Lisa, is composing a letter to the editor about her 20-year fight to stay alive.

“I know how tall the bridge is. I know how many seconds it takes to land,” Lisa said.

Lisa is an attorney with severe depression. Conventional medicines could not suppress her suicidal thoughts.

“It’s awful,” she said. “The day starts with waking up thinking ‘Can I even get out of bed?’ You just fight it to exhaustion every single day.”

She was referred to Dr. David Feifel who NBC 7 first also spoke to three years ago. Patients travel from as far away as Canada to undergo his Ketamine therapy.

“Sort of a psychedelic experience. It’s also been termed dissociative experience because it is sort of an out-of-body feeling,” Dr. Feifel said of his therapy.

Dr. Feifel says low doses of Ketamine have an almost immediate effect on his patients, unlike conventional anti-depressants that can take weeks to build up a therapeutic level.

While Ketamine doesn’t stay in the body more than a day, its effects can last for months.

“It seems to be able to vaporize people’s sense of wanting to take their life.” Dr. Feifel said.

Lisa has received some 35 treatments over the last four months.

“I walk in here crappy, I’ll leave happy. It is a remarkable, remarkable experience that in 20 years nothing has ever come close” Lisa said.

Her goal is to need fewer treatments and experience longer-lasting effects.

Lisa’s hope for the so-called “untreatable community” of depressed people is they find help.

Ketamine-Associated Brain Changes – A Review of the Neuroimaging Literature

KEY POINTS:

                  Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature

Subanesthetic doses of ketamine have rapid (within hours), robust (across a variety of symptoms), and relatively sustained (typically up to one week) antidepressant effects—even in patients with TRD (treatment resistant depression). Clinical studies show that about 50% of patients with TRD have a significant decrease in symptoms within 24 hours of a single intravenous subanesthetic ketamine dose.

Animal models show that ketamine’s antidepressant effects are likely mediated by its antagonism of N-methyl-D-aspartate (NMDA) receptors through increased α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA)–mediated glutamatergic signaling. This triggers activation of intracellular synaptogenic pathways, most notably in the mechanistic target of rapamycin (mTOR)–signaling pathway, which also has implications in many other psychiatric disorders.

With regard to MDD patients, decreased glutamate has been noted in various prefrontal regions, including the dorsolateral prefrontal cortex (dlPFC), dorsomedial PFC (dmPFC), and anterior cingulate cortex (ACC), when compared to controls.8–10 This shortage of glutamate makes ketamine an ideal treatment for MDD; by creating a surge in glutamate levels in regions of the brain that suffer from a glutamate deficit, ketamine may provide some normalization of glutamate levels in patients with MDD. This “glutamate surge” hypothesis has dominated as the primary theory of ketamine’s antidepressant mechanism.

Ketamine may work through additional receptors, as it is known to have effects on several opioid receptors, adrenergic receptors, and several serotonin and norepinephrine transporters.17–19 It is also possible that acute dissociative side effects of ketamine may be mediating antidepressant response.

One salient biological metric that may provide insight into ketamine’s mechanism of action is related to dissociation. Dissociative side effects begin from infusion, reach a peak typically within an hour of infusion, and are completely diminished 230 minutes after infusion.20 The same study has shown that increased dissociation and psychotomimetic symptoms immediately following infusion may predict antidepressant response. (Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord 2014;159:56–61Do the dissociative side effects of ketamine mediate its antidepressant effects.)

Certain themes have emerged with Ketamine. First are our findings of convergent brain regions implicated in MDD and how ketamine modulates those areas. Specifically, the subgenual ACC has been a region of interest in many previous studies. In relation to emotion and cognition, ketamine appears to reduce brain activation in regions associated with self-monitoring, to increase neural regions associated with emotional blunting, and to increase neural activity in reward processing.

Overall, ketamine’s effects were most notably found in the subgenual ACC, PCC, PFC, and hippocampus. Abnormalities in overlapping regions (specifically, the dorsal and subgenual ACC, amygdala, hippocampus, and ventral striatum) have been implicated, via a growing body of neuroimaging literature, in the pathophysiology of depression.  The subgenual ACC, in particular, has been a frequently studied area of interest concerning ketamine and MDD.

FMRI found significant reductions in subgenual ACC coupling with hippocampus, retrosplenial cortex, and thalamus. Immediate reductions in subgenual ACC blood flow and focal reductions in OFC blood flow strongly predicted dissociation.

NIMH studies using PET 120 minutes postinfusion found that increased metabolism in the subgenual ACC was positively correlated with improvements in depression scores post-ketamine. (Neural correlates of rapid antidepressant response to ketamine in bipolar disorder..)

Analysis of resting-state scans in healthy volunteers further suggests that dissociation may be responsible for ketamine’s antidepressant effects because it may disconnect the “excessive effects of an aversive visceromotor state on cognition and the self”—a hallmark of depression.40(p 163) Related, one study found that ketamine may dampen brain regions involved in rumination (the repetitive focusing of attention on negative feelings and thoughts in response to negative mood) by reducing the functional connectivity between the pregenual ACC and the dorsal PCC, and decreasing connectivity between the left and right executive-control networks.  (. Lehmann M, Seifritz E, Henning A, et al. Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network. Soc Cogn Affect Neurosci 2016;11:1227–35 .Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network.)

Taken together, these studies suggest that ketamine may cause a “disconnect” in several circuits related to affective processing, perhaps by shifting focus of attention away from the internal states of anxiety, depression, and somatization, and more toward the perceptual changes (e.g., hallucinations, visual distortions, derealization) induced by ketamine. Similarly, during an emotion task, ketamine attenuated responses to negative pictures, suggesting that the processing of negative information is specifically altered in response to ketamine. (Scheidegger M, Henning A, Walter M, et al. Ketamine administration reduces amygdalo-hippocampal reactivity to emotional stimulation. Hum Brain Mapp 2016;37:1941–52.Ketamine administration reduces amygdalo‐hippocampal reactivity to emotional stimulation)

By taking the focus off “oneself” and placing it on other stimuli, it is possible that ketamine decreases awareness of negative experiences and consequently improves mood.

Perhaps most interesting are ketamine’s effects on brain connectivity as it relates to self-monitoring behaviors. Reduced connectivity between the pregenual ACC and dorsal PCC was associated with increased dissociation during infusion, and reduced activation in the left superior temporalcortex was associated with impaired self-monitoring56,65—which is disruptive to patients with psychotic illness—especially those with chronic symptoms of psychosis. By contrast, the transient dissociation experienced by depressed patients during a ketamine infusion may have the effect of dampening what the hyperactive self-monitoring associated with depressive illness (Lehmann M, Seifritz E, Henning A, et al. Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network. Soc Cogn Affect Neurosci 2016;11:1227–35Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network. b)

During ketamine administration, subjects experience emotional blunting, which may be associated with reduced limbic responses to emotional stimuli.54,55 It is possible that by decreasing the activity of deep limbic structures (thought to be involved in the pathophysiology of depression, such as the amygdala), ketamine acutely disables the emotional resources required to perpetuate the symptoms of depression. (Abel KM, Allin MP, Kucharska-Pietura K, et al. Ketamine and fMRI BOLD signal: distinguishing between effects mediated by change in blood flow versus change in cognitive state. Hum Brain Mapp 2003;18:135–45. Ketamine and fMRI BOLD signal Distinguishing between effects mediated by change in blood flow versus change in cognitive state|||| Abel KM, Allin MP, Kucharska-Pietura K, et al. Ketamine alters neural processing of facial emotion recognition in healthy men: an fMRI study. Neuroreport 2003;14:387–91 Ketamine alters neural processing of facial emotion recognition in healthy men an fMRI study.)

Ketamine may play a role in reactivating reward areas of the brain in patients with MDD. This reactivation may be especially important, as reward areas in MDD have been characterized by decreased subcortical and limbic activity and by an increased cortical response to reward paradigms. (Zhang WN, Chang SH, Guo LY, Zhang KL, Wang J. The neural correlates of reward-related processing in major depressive disorder: a meta-analysis of functional magnetic resonance imaging studies. J Affect Disord 2013;151:531–9.)

In resting-state scans, BOLD activation in the cingulate gyrus, hippocampus, insula, thalamus, and midbrain increased after ketamine.( Stone J, Kotoula V, Dietrich C, De Simoni S, Krystal JH, Mehta MA. Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe. J Psychopharmacol 2015;29:1025–8.Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe)

In addition, ketamine increases neural activation in the bilateral MCC, ACC, and insula, as well as the right thalamus.  Activation of these areas is consistent with activation of reward-processing areas, suggesting that ketamine may play a role in activating reward neurocircuitry. (Hoflich A, Hahn A, Kublbock M, et al. Ketamine-dependent neuronal activation in healthy volunteers. Brain Struct Funct 2017;222:1533–42.)

Though no single brain area has been singled out as the locus of depression, ketamine affects different areas of the brain in various ways, which may contribute to overall mood improvements. For example, at baseline, patients with MDD, compared to healthy volunteers, had reduced global connectivity in the PFC and increased connectivity in the posterior cingulate, precuneus, lingual gyrus, and cerebellum; postketamine, responders had increased connectivity in the lateral PFC, caudate, and insula. (Abdallah CG, Averill LA, Collins KA, et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology 2017;42:1210–9.Ketamine Treatment and Global Brain Connectivity in Major Depression.)

These findings may reflect ketamine’s ability to reclaim frontal control over deeper limbic structures, thus strengthening the cognitive control of emotions and decreasing depressive symptoms. Similarly, TRD patients, compared to healthy volunteers, had reduced insula and caudate responses to positive emotions at baseline, which normalized in the caudate post-ketamine. (Murrough JW, Collins KA, Fields J, et al. Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Transl Psychiatry 2015;5:e509 Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder.)

Improvements are correlated with increased metabolism in the hippocampus, dorsal ACC, and decreased metabolism in the OFC. (Lally N, Nugent AC, Luckenbaugh DA, Niciu MJ, Roiser JP, Zarate CA Jr. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J Psychopharmacol 2015;29:596–607 Neural correlates of change in major depressive disorder anhedonia following open-label ketamine.)

Specifically, based on this review, future studies should likely focus on ketamine’s action in the subgenual ACC, PCC, PFC, and hippocampus. Another promising direction for research builds on the view that depression is the product of underactive prefrontal and limbic mood-regulation networks and overreactive subcortical limbic networks, which are involved in emotional and visceral responses. (Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 2008; 213:93–118 Brain structural and functional abnormalities in mood disorders.)

Ketamine’s potential use in both research and treatment is promising indeed.

 

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The Effect of a Single Dose of Intravenous Ketamine on suicidal ideation – systemic review and meta-analysis

Rapid-Acting Antidepressants Mechanistic Insights and Future Directions.

Ketamine and rapid-acting antidepressants a new era in the battle against depression and suicide.

Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine

A Circadian Genomic Signature Common to Ketamine and Sleep Deprivation in the Anterior Cingulate Cortex

New Targets for Rapid Antidepressant Action

Role of copper in depression. Relationship with ketamine treatment

Ketamine normalizes brain activity during emotionally valenced attentional processing in depression.

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine.

Recognizing Depression from the Microbiota⁻Gut⁻Brain Axis. b

Psychobiotics and the gut–brain axis in the pursuit of happines

Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion

Default Mode Connectivity in Major Depressive diosrder measured up to 10 days after Ketamine administration

S-Adenosyl Methionine and Transmethylation Pathways in Neuropsychiatric Diseases Throughout Life

S-Adenosyl Methionine in the Therapy of Depression and Other Psychiatric Disorders.

Ketamine for Depression, 2 Diagnostic and Contextual Indications.

Ketamine’s antidepressant efficacy is extended for at least four weeks in subjects with a family history of an alcohol use disorder

Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder

The role of adipokines in the rapid antidepressant effects of ketamine.

response to ketamine and prediction of treatment outcome

What is the mechanism of Ketamine’s rapid‐onset antidepressant effect A concise overview of the surprisingly large number of possibilities

Medical comorbidity in bipolar disorder The link with metabolic-inflammatory systems.

Sterile Inflammation of Brain, due to Activation of Innate Immunity, as a Culprit in Psychiatric Disorders

Sterile Inflammation of Brain, due to Activation of Innate Immunity, as a Culprit in Psychiatric Disorders

Role of neuro-immunological factors in the pathophysiology of mood disorders.

Anti-inflammatory agents in the treatment of bipolar depression a systematic review and meta-analysis

The role of tryptophan metabolism and food craving in the relation between obesity and bipolar disorder

Immune-based strategies for mood disorders facts and challenges

Metabolic syndrome in psychiatric patients implications

Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders

The Impact of a Single Nucleotide Polymorphism in SIGMAR1 on Depressive Symptoms in Major Depressive Disorder and Bipolar Disorder.

Case–control association study of 14 variants of CREB1, CREBBP and CREM on MDD and bipolar

Metabolic syndrome in psychiatric patients overview, mechanisms, and implications.

Peripheral inflammation, Physical Activity and Cognition in Bipolar Disorder

The putative role of oxidative stress and inflammation in the pathophysiology of sleep dysfunction across neuropsychiatruc disorders – chronic fatigue bipolar MS

Bipolar Disorder and Inflammation.

Pharmacologic implications of inflammatory comorbidity in bipolar disorder.

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Molecular and Cellular Effects of Traumatic Stress Implications for PTSD

Synaptic Loss and the Pathophysiology of PTSD Implications for Ketamine as a Prototype Novel Therapeutic

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CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

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Below is a recent study regarding the treatment of adolescents with Ketamine for refractory depression. There seems to be good success and longer lasting results:

Intravenous Ketamine for Adolescents with Treatment-Resistant Depression: An Open-Label Study

The average response rate in published studies testing ketamine for adult TRD is 67% (Wan et al. 2015), which is considerably higher than TRD interventions (e.g., the average response rate for transcranial magnetic stimulation is 45%
(Conelea et al. 2017).

Background: Novel interventions for treatment-resistant depression (TRD) in adolescents are urgently needed. Ketamine has been studied in adults with TRD, but little information is available for adolescents. This study investigated efficacy and tolerability of intravenous ketamine in adolescents with TRD, and explored clinical response predictors.

Methods: Adolescents, 12–18 years of age, with TRD (failure to respond to two previous antidepressant trials) were administered six ketamine (0.5 mg/kg) infusions over 2 weeks. Clinical response was defined as a 50% decrease in Children’s Depression Rating Scale-Revised (CDRS-R); remission was CDRS-R score ≤28. Tolerability assessment included monitoring vital signs and dissociative symptoms using the Clinician-Administered Dissociative States Scale (CADSS).

Results: Thirteen participants (mean age 16.9 years, range 14.5–18.8 years, eight biologically male) completed the protocol. Average decrease in CDRS-R was 42.5% (p = 0.0004). Five (38%) adolescents met criteria for clinical response. Three responders showed sustained remission at 6-week follow-up; relapse occurred within 2 weeks for the other two responders. Ketamine infusions were generally well tolerated; dissociative symptoms and hemodynamic symptoms were transient. Higher dose was a significant predictor of treatment response.

Conclusions: These results demonstrate the potential role for ketamine in treating adolescents with TRD. Limitations include the open-label design and small sample; future research addressing these issues are needed to confirm these results. Additionally, evidence suggested a dose–response relationship; future studies are needed to optimize dose. Finally, questions remain regarding the long-term safety of ketamine as a depression treatment; more information is needed before broader clinical use.

Intravenous Ketamine for Adolescents – PDF

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Ketamine has much support in the use of hard-to-treat depression and suicidal behaviors. Below are studies and their links, including a meta-analysis, which demonstrate the effect of Ketamine. Also a recent trial by Carlos Zarate shows the heterogenous nature of response to Ketamine . It is difficult to say who is going to be lifted from their depression completely or partially respond, but in the study, Dr. Zarate showed that patients with a long history of suicidal thinking and self-harm will have less of a response in some cases.

NOVA Health Recovery | 703-844-0184 | Fairfax, Virginia 22304
NOVA Health Recovery | 703-844-0184 | Fairfax, Virginia 22304

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

Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients

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

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

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

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

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

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

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

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

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

 

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

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

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

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

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

“There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm,” said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. “Currently available antidepressants can be effective in reducing suicidal thoughts in patients with depression, but they can take weeks to have an effect. Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients.”

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

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

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

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

“This study shows that ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression,” said Dr. Grunebaum. “Additional research to evaluate ketamine’s antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster acting and have the potential to help individuals who do not respond to currently available treatments.”

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

Ketamine for depression | PTSD | 703-844-0184 | NOVA Health Recovery | Fairfax, Virginia 22304
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Ketamine as a Potential Treatment for Suicidal Ideation A Systematic Review of the Literature 2015

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

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

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Characterizing the course of suicidal ideation response to ketamine

Characterizing the course of suicidal ideation response to ketamine PDF

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

 

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

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

 

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Glycine has a calming effect on the brain – it helps you wind down and prepare for sleep – its role as an inhibitory neurotransmitter has been unfolding over many years of ongoing research efforts. Easily one of the most versatile amino acids, glycine serves as a building block to proteins (collagen, the most abundant protein in our body, is one-third glycine), and is heavily utilized for the production of heme, DNA and RNA synthesis, glutathione formation, and for enriching the body’s capacity for methylation reactions [1] [2]. Sleep Problems People need sleep. It is our basic human need. Too many of us experience sleep problems. Laying there restless, counting sheep, watching the hostile glow of the green numbers, fearing the absence of sleep – this dreaded scenario of sleep-deprived desperation is all too familiar. Needless to say, sleep issues have become a pervasive health problem, and research shows that lack of sleep affects everything from mental competence to increased risk of chronic diseases and cancer.

Glycine Promotes Sleep Without Altering Sleep Architecture

When human volunteers who have continuously experienced unsatisfactory sleep were given 3 g glycine before bedtime, their sleep improved [3]. Using polysomnography, a type of diagnostic tool in sleep studies, glycine was shown to shorten the amount of time to fall asleep and stabilize sleep state, with no alterations in sleep architecture, unlike with traditional hypnotic drugs. Glycine promoted normal nocturnal sleep cycles, from deeper to shallower with very few interruptions.

Glycine Lowers Core Body Temperature

So what is it about this tiny amino acid that could be so powerful in contributing to regulating such a complex process as sleep? First of all, glycine taken orally has easy access to the brain – it readily crosses the blood brain barrier via glycine transporters [4].Once in the brain, glycine targets glutamate NMDA receptors in the suprachiasmatic nucleus (SCN) – the 24-hour biological clock in the central nervous system that controls when we want to be asleep and awake. By modulating NMDA receptors in the SCN, glycine induces vasodilation throughout the body to promote lowering of core body temperature [5]. Sleep and body temperature are intertwined – in its circadian oscillation, body temperature decreases before the onset of sleep and continues to decrease throughout the night, reaching its nadir about 2 hours after sleep onset, and gradually rising as a person wakes [6]. Temperature is just one of many 24-hour rhythms our bodies experience throughout the day and as nighttime approaches – the drop is important for initiating sleep. Glycine’s effect on thermoregulation is similar to that of common prescription sleep medications that also work by reducing core body temperature to promote sleep [7] [8].

Unlike many sleep aids out there, nutraceutical or pharmaceutical, that promote sleep and leave you groggy the next day, glycine actually corrects feelings of fatigue and sleepiness during the day.

Additional mechanisms that glycine may rely on to promote sleep include inhibiting orexin neurons – the “wakefulness” neurons (the absence of which is implied in narcolepsy) [9]. However, more research is needed to fully elucidate this process.

Glycine Improves Daytime Performance

Here’s the exciting part – unlike many sleep aids out there, nutraceutical or pharmaceutical, that promote sleep and leave you groggy the next day, glycine actually corrects feelings of fatigue and sleepiness during the day [10]. Sleep-restricted volunteers receiving glycine, after waking, showed improved reaction times in in the psychomotor vigilance test compared to the placebo group and reported feeling refreshed.

Glycine Regulates Daytime Wakefulness

Glycine was found to contribute to yet another circadian process – stimulating the expression of arginine vasopressin – a neuropeptide produced in the SCN. Animal studies show that the expression levels of arginine vasopressin were increased during the day in the glycine treatment group [10]. Arginine vasopressin serves as an output signal of the hypothalamic biological clock, an important modulator of circadian processes involving the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes and the autonomic nervous system [11]. Specifically to the HPA axis, arginine vasopressin synergizes signaling with corticotropin releasing hormone (CRH) to facilitate the release of adrenocorticotropic hormone (ACTH) to ultimately trigger the production of cortisol from the adrenal glands, thus contributing to the state of wakefulness [12]. Sleep isn’t just a time to rest. It’s an active process of cleaning out toxins and repairing brain cells damaged by free radicals [13]. Think about sleep as a form of neural sanitization – during sleep, waste products of brain metabolic processes are removed from the tiny spaces between brain cells where they can accumulate [14]. Sleep, therefore, is a kind of a power cleanse that restores and rejuvenates our brain for optimal function [15]. Considering glycine’s prominent role in detoxifications processes, as future research studies unfold, it would be exciting to see what additional processes glycine helps regulate to support a healthy brain.

References

[1] M.A. Razak, P.S. Begum, B. Viswanath, S. Rajagopal, Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review, Oxid Med Cell Longev 2017 (2017) 1716701.Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine A Review [2] M.F. McCarty, J.H. O’Keefe, J.J. DiNicolantonio, Dietary Glycine Is Rate-Limiting for Glutathione Synthesis and May Have Broad Potential for Health Protection, Ochsner J 18(1) (2018) 81-87.Dietary Glycine Is Rate-Limiting for Glutathione Synthesis and May Have Broad Potential for Health Protection. [3] W.I. Yamadera, K.; Chiba, S.; Bannai, M.; Takahashi, M., Nakayama, K., Glycine ingestion improves subjective sleep quality in human volunteers, correlating with polysomnographic changes, Sleep and Biological Rhythms 5 (2007).Glycine ingestion improves subjective sleep quality in human volunteers, correlating with polysomnographic changes [4] A. Kurolap, A. Armbruster, T. Hershkovitz, K. Hauf, A. Mory, T. Paperna, E. Hannappel, G. Tal, Y. Nijem, E. Sella, M. Mahajnah, A. Ilivitzki, D. Hershkovitz, N. Ekhilevitch, H. Mandel, V. Eulenburg, H.N. Baris, Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine, Am J Hum Genet 99(5) (2016) 1172-1180. [5] N. Kawai, N. Sakai, M. Okuro, S. Karakawa, Y. Tsuneyoshi, N. Kawasaki, T. Takeda, M. Bannai, S. Nishino, The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus, Neuropsychopharmacology 40(6) (2015) 1405-16.The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus. [6] M. Bannai, N. Kawai, New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep, J Pharmacol Sci 118(2) (2012) 145-8.New Therapeutic Strategy for Amino Acid Medicine – glycine improves sleep [7] R.R. Markwald, T.L. Lee-Chiong, T.M. Burke, J.A. Snider, K.P. Wright, Jr., Effects of the melatonin MT-1/MT-2 agonist ramelteon on daytime body temperature and sleep, Sleep 33(6) (2010) 825-31. [8] E.E. Elliot, J.M. White, The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry, Neuropharmacology 40(5) (2001) 717-21. [9] M. Hondo, N. Furutani, M. Yamasaki, M. Watanabe, T. Sakurai, Orexin neurons receive glycinergic innervations, PLoS One 6(9) (2011) e25076. [10] M. Bannai, N. Kawai, K. Ono, K. Nakahara, N. Murakami, The effects of glycine on subjective daytime performance in partially sleep-restricted healthy volunteers, Front Neurol 3 (2012) 61.The Effects of Glycine on Subjective Daytime Performance in Partially Sleep-Restricted Healthy Volunteers [11] A. Kalsbeek, E. Fliers, M.A. Hofman, D.F. Swaab, R.M. Buijs, Vasopressin and the output of the hypothalamic biological clock, J Neuroendocrinol 22(5) (2010) 362-72. [12] H.K. Caldwell, E.A. Aulino, K.M. Rodriguez, S.K. Witchey, A.M. Yaw, Social Context, Stress, Neuropsychiatric Disorders, and the Vasopressin 1b Receptor, Front Neurosci 11 (2017) 567.Social Context, Stress, Neuropsychiatric Disorders, and the Vasopressin 1b Receptor. [13] A.R. Eugene, J. Masiak, The Neuroprotective Aspects of Sleep, MEDtube Sci 3(1) (2015) 35-40.Sleep Facilitates Clearance of Metabolites from the Brain [14] L. Xie, H. Kang, Q. Xu, M.J. Chen, Y. Liao, M. Thiyagarajan, J. O’Donnell, D.J. Christensen, C. Nicholson, J.J. Iliff, T. Takano, R. Deane, M. Nedergaard, Sleep Drives Metabolite Clearance from the Adult Brain, Science 342(6156) (10/18/2013) 373-377. [15] A.R. Mendelsohn, J.W. Larrick, Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases, Rejuvenation Res 16(6) (2013) 518-23.   __________________________________________________________________________________________

NUTRITIONAL INTERVENTIONS TO help sleep

KEY POINTS • Given the importance of sleep for optimal health and performance, a number of nutritional interventions has been investigated to determine their effectiveness in enhancing sleep quality and quantity. • As some nutritional interventions may exert effects on neurotransmitters that are involved in the sleep-wake cycle, it is possible that these interventions may enhance sleep. • High glycemic index foods may be beneficial for improving sleep if consumed more than 1 h prior to bedtime and solid meals may be better than liquid meals at enhancing sleep. • From the current literature, it appears that diets high in carbohydrate may result in shorter sleep latencies, while diets high in protein may result in improved sleep quality and diets high in fat may negatively influence total sleep time. • Tryptophan, melatonin and valerian are other substances that have some scientific evidence for enhancing sleep. BACKGROUND While the exact function of sleep is not fully understood, sleep has extremely important biological functions. This is demonstrated by the negative effects that sleep deprivation can have on performance, learning, memory, cognition, pain perception, immunity, inflammation, glucose metabolism and neuroendocrine function. A number of nutritional substances have traditionally been associated with promoting sleep. Researchers have recently begun to investigate their effectiveness as a substitute for pharmacological interventions. SLEEP OVERVIEW Sleep Stages Sleep can be defined as a reversible behavioural state where an individual is perceptually disengaged from and unresponsive to the environment (Carskadon & Dement, 2011). Sleep is a complex physiological and behavioural state that has two basic states based on physiological parameters. These are rapid eye movement (REM) and non-REM (NREM). An electroencephalogram (EEG), in which electrodes measures brain electrical activity, is used to identify the two states (Figure 1). NREM sleep is divided into four stages (1- 4) which are associated with a progressive increase in the depth of sleep (Carskadon & Dement, 2011). REM sleep is characterised by muscle atonia, bursts of rapid eye movement and dreaming. Therefore, REM sleep is an activated brain in a paralysed body. Measuring Sleep There are two commonly used methods to assess sleep. The first is actigraphy and it involves monitors on the wrist, which are worn like a wristwatch that continuously record body movement (usually stored in 1-min periods), and the recording of sleep diaries, where participants record the start and end times and dates for all sleep periods (i.e., nighttime sleeps and daytime naps). Data from sleep diaries and activity monitors are used to determine when participants are awake and when they are asleep. Essentially, all time is scored as awake unless (i) the sleep diary indicates that the participant was lying down attempting to sleep and (ii) the activity counts from the monitor are sufficiently low to indicate that the participant was immobile. When these two conditions are satisfied simultaneously, time is scored as sleep. Actigraphy is useful for understanding sleep patterns as it is noninvasive and relatively easy to collect data over significant periods of time (commonly 2 wk of monitoring). Figure 1. The progression of sleep stages across a single night in a normal young adult volunteer is illustrated in this sleep histogram. The text describes the ideal or average pattern (Carskadon & Dement, 2011). The second method is polysomnography (PSG), by which body functions such as brain activity (EEG), eye movements (EOG), muscle activity (EMG) and cardiac activity (ECG) are measured. PSG provides information on sleep staging and is considered the “gold standard” for assessing sleep quality and quantity. PSG can be expensive, is labour intensive and is often used primarily for assessing clinical sleep disorders. NUTRITIONAL INTERVENTIONS TO ENHANCE SLEEP There are a number of neurotransmitters in the brain that are involved in the sleep-wake cycle. These include serotonin, gammaaminobutyric acid (GABA), orexin, melanin-concentrating hormone, cholinergic, galanin, noradrenaline and histamine (Saper et al., 2005). Therefore, it is possible that nutritional interventions that act upon these neurotransmitters in the brain may also influence sleep. Dietary precursors can influence the rate of synthesis and function of a small number of neurotransmitters, including serotonin (Silber & Schmitt, 2010). Figure 2 below depicts the means by which diet may influence the central nervous system and through the production of serotonin (5-HT) and melatonin. Synthesis of 5-HT is dependent on the availability of its precursor in the brain, the amino acid L-tryptophan (Trp). Trp is transported across the bloodbrain barrier by a system that shares other transporters including a number of large neutral amino acids (LNAA). Thus, the ratio of Trp/ LNAA in the blood is crucial to the transport of Trp into the brain and an increase in this ratio can be achieved by the intake of pure tryptophan or tryptophan-rich protein (Silber & Schmitt, 2010). The food protein with the highest Trp content and most favourable Trp:LNAA ratio is α-lactalbumin, a whey-derived protein (Heine, 1999). Ingestion of other forms of protein generally decrease the uptake of Trp into the brain, as Trp is the least abundant amino acid and, therefore, other LNAA are preferentially transported into the brain. Carbohydrate, however, increases brain Trp via insulin stimulation of LNAA into skeletal muscle, which results in an increase in free-Trp (Fernstrom & Wurtman, 1971). Carbohydrate A small number of studies have investigated the effects of carbohydrate (CHO) ingestion on indices of sleep quality and quantity. Porter and Horne (1981) provided six male subjects with either a high CHO meal (130 g), a low CHO meal (47 g) or a meal containing no CHO, 45 min prior to bedtime. The high CHO meal resulted in increased REM sleep, decreased light sleep and wakefulness (Porter & Horne, 1981). However, the caloric content of the meals was not matched in this study making it impossible to tell whether the effect was due to the carbohydrate or the calories. The effect of meal vs. drink (with high, normal and low CHO contents) vs. water at various time intervals prior to sleep has also been studied (Orr et al, 1997). Results demonstrated that solid meals enhanced sleep onset latency (time taken to fall asleep) up to 3 h after ingestion and the liquid meal was slightly better than water. There was no effect of meal or drink composition on sleep. From this study, it cannot be concluded that the observed effects are an effect of carbohydrate or energy. Afaghi et al. (2007, 2008) conducted two studies investigating CHO ingestion prior to sleep in healthy males. In the first study, high or low Glycemic Index (GI) meals were given 4 h or 1 h prior to sleep (Afaghi et al., 2007). The high GI meal significantly improved sleep onset latency over that of the low GI meal. In addition, providing the meal at 4 h prior to sleep was better than a meal at 1 h prior to sleep. In the second study, a very low CHO meal (1% CHO, 61% fat, 38% protein) was compared to a control meal (72% CHO, 12.5% fat, 15.5% protein) matched for energy, 4 h prior to sleep (Afaghi et al., 2008). The very low CHO meal increased the percentage of time spent in slow wave sleep (stages 3 and 4 of NREM), and the time spent in REM sleep when compared to the control condition. Finally, Jalilolghadr et al. (2011) provided eight children with either a high GI (200 mL milk and glucose) or lower GI drink (200 mL milk and honey), 1 h prior to bedtime. In this study, the high GI drink increased arousal to a greater extent than the low GI drink, suggesting a poorer quality of sleep. From the limited and somewhat contradictory nature of the above studies, it appears that high GI foods may be beneficial if consumed more than 1 h prior to bedtime, and that solid meals may be better than liquid meals at enhancing sleep. Sports Science Exchange (2013) Vol. 26, No. 116, 1-5 3 Acute Mixed Composition Meals Only a small number of studies have investigated the effects of meals or drinks of varying composition on sleep. Hartmann et al. (1979) provided a drink with the evening meal which was either high fat (90 g), high CHO (223 g) or high protein (30 g). The findings revealed no effect of any of the drinks on sleep when compared to no drink. Zammit et al. (1995) examined the effects of high vs. low energy liquid meals (993.5 vs. 306 Kcal) provided at lunch, compared to no meal on daytime naps. Both liquid meals demonstrated increased time in stages 2 and 3 of NREM sleep when compared to no meal. However, there were no differences in sleep onset latency (Zammit et al., 1995). Again, there is very limited research in this area, but it appears that reduced caloric intake may result in poor sleep. Habitual Diet The above-mentioned studies have examined acute nutritional manipulations on sleep. There has also been research conducted that investigated chronic manipulations or habitual dietary intake. Kwan et al. (1986) provided six healthy females with a low CHO (50 g/day) diet for 7 d and reported increased REM latency when compared to sleep prior to the 7 d intervention when the subjects consumed their usual diet. Lacey et al. (1978) also studied females for 7 d with either high protein (>100 g), low protein (<15 g) or normal daily protein intakes. Results showed that high protein intakes resulted in increased restlessness, while low protein intakes resulted in reduced amounts of slow wave sleep. However, there were no differences in total sleep time (Lacey et al., 1978). While it is difficult to draw definitive conclusions from this study, it is clear that altering daily protein intake may affect sleep quality. In a recent comprehensive study, Lindseth et al. (2011) manipulated the diet of 44 adults for 4 d. Diets were either high protein (56% protein, 22% CHO, 22% fat), high CHO (22% protein, 56% CHO, 22% fat) or high fat (22% protein, 22% CHO, 56% fat). Diets higher in CHO resulted in shorter sleep onset latencies and diets higher in protein resulted in fewer wake episodes. There was little effect of the high fat diet on markers of sleep quality and quantity (Lindseth et al., 2011). Finally, Grandner et al. (2010) examined the dietary intake (through questionnaires) of 459 postmenopausal women over 7 d. The only significant finding of this study was that fat intake was negatively associated with total sleep time (Grandner et al., 2010). From the above studies, it appears that diets high in carbohydrate may result in shorter sleep latencies, while diets high in protein may result in improved sleep quality and diets high in fat may negatively influence total sleep time. However, additional research is necessary in this area. Tryptophan As mentioned above, the synthesis of 5-HT in the brain is dependent on the availability of its precursor Trp. Further, 5-HT is a precursor to melatonin in the pineal gland (Silber & Schmitt, 2010). There have been numerous studies investigating the effects of tryptophan supplementation on sleep (for review, see Silber & Schmitt, 2010) and it appears that doses of Trp as low as 1 g can improve sleep latency and subjective sleep quality. This can be achieved by consuming ~300 g of turkey or ~200 g of pumpkin seeds. Melatonin Melatonin is a hormone that is associated with circadian rhythms (Morin & Benca, 2012) and some research has demonstrated sedative/hypnotic effects of this compound (Buscemi et al., 2005). However, research investigating the use of melatonin for primary insomnia demonstrates inconclusive results (Morin & Benca, 2012). A meta-analysis reported a reduction in sleep onset latency of 7.2 min and concluded that while melatonin appeared safe for short-term use, there was no evidence that melatonin was effective for most primary sleep disorders (Buscemi et al., 2005). Another recently investigated intervention is tart cherry juice. Tart cherries contain high concentrations of melatonin and when consumed over a 2 wk period improved subjective insomnia symptoms when compared to placebo (Pigeon et al., 2010). There have also been reports of modest improvements in sleep time and quality (Howatson et al., 2011). Valerian Valerian is an herb that binds to GABA type A receptors and is thought to induce a general calming effect on the body (Wheatley, 2005). Results of a meta-analysis showed subjective improvement in sleep quality, but not quantity (Fernandez-San-Martin et al., 2010). Other Nutritional Interventions Nucleotides are believed to be involved in the physiological function of sleep, in particular uridine monophosphate (5’UMP) and adenosine monophosphate (5’AMP). 5’UMP causes a depressive effect on the central nervous system and one study that administered low doses prior to sleep reported improvements in some sleep indices (Chagoya de Sanchez et al., 1996). 5’AMP has hypnotic properties and levels of this nucleotide decline during wakefulness (Sanchez et al., 2009). 5’AMP acts on the adenosine A2A receptors in the venterolateral nuclei region of the brain, which is believed to be related to insomnia, pain and depression (Cubero et al., 2009). These nucleotides have been studied via investigations regarding the possible hypnotic effects of infant formula (Sanchez et al., 2009). In this study, the sleep-promoting formula contained high levels of L-tryptophan and carbohydrates, low levels of protein, and 5’UMP and 5’AMP. Fiftyfour children were monitored over 1 wk using actigraphy, with results showing increased time in bed and increased sleep efficiency. Sports Science Exchange (2013) Vol. 26, No. 116, 1-5 4 The authors suggested that these results supported the concept of chrononutrition, i.e., the influence of time of day at which food is ingested having effects on different biological rhythms, such as sleep and wakefulness. However, no blood measures were made and thus it was not possible to determine whether the ingested compounds were transported from the digestive system to the bloodstream and which of the ingredients were actively involved in enhancing sleep. Glycine (a non-essential amino acid) functions as an inhibitory neurotransmitter in the central nervous system and also acts as a co-agonist of glutamate receptors. Glycine has been shown to improve subjective sleep in a recent Japanese study (Bannai et al., 2012). Yamadera et al. (2007) also reported shorter sleep onset latencies measured by polysomnography (“gold standard” for sleep assessment). The authors speculated from previous studies on rodents that potential mechanisms may involve increased vasodilation and thus lowering of core temperature, and increased extracellular serotonin release in the prefrontal cortex of the brain (Yamadera et al., 2007). L-theanine is an amino acid analogue present in tea but not coffee that demonstrates pharmacological actions such as promoting feelings of calmness and reduced alertness. One study reported that L-theanine partially counteracted the caffeine-induced decrease in slow wave sleep in rats (Jang et al., 2012). There are also numerous other traditional products that are purported sleep aids including passionflower, kava, St. John’s wort, lysine, magnesium, lavender, skullcap, lemon balm, magnolia bark, 5-HTP and GABA. While the majority of these products have not been adequately investigated in the scientific literature, many can be found in sleep aid supplements that can be purchased over-the-counter in pharmacies and health food suppliers. However, like many available supplements, there is always the danger that these purported sleep aids may contain illegal substances and thus should be used with caution. PRACTICAL APPLICATIONS Athletes should focus on utilising good sleep hygiene to maximise sleep (See previous Sports Science Exchange article on “Sleep in Elite Athletes”). While research is minimal and somewhat inconclusive, several practical recommendations may be suggested: • High glycemic index (GI) foods such as white rice, pasta, bread and potatoes may promote sleep. However, they should be consumed more than one hour prior to bedtime. • Diets high in carbohydrate may result in shorter sleep latencies. • Diets high in protein may result in improved sleep quality. • Diets high in fat may negatively influence total sleep time. • When total caloric intake is decreased, sleep quality may be disturbed. • Small doses of tryptophan (1 g) may improve both sleep latency and sleep quality. This can be achieved by consuming ~300 g of turkey or ~200 g of pumpkin seeds. • The hormone melatonin and foods that have a high melatonin concentration may decrease sleep onset time. • Subjective sleep quality may be improved with the ingestion of the herb valerian. SUMMARY While the quantity of research investigating the effects of nutritional interventions on sleep is increasing, future research needs to highlight the importance of nutritional and dietary interventions to enhance sleep both in the general population and in athletes. Careful examination of both the timing of food ingestion and the use of different interventions would provide invaluable information to athletes on how to improve sleep through nutritional means. Ideally, research will lead to nutritional interventions for optimising both sleep quality and quantity, as well as enhancing athlete recovery from training and competition. Sports Science Exchange (2013) Vol. 26, No. 116, 1-5 5 REFERENCES Afaghi, A., H. O’Connor, and C.M. Chow (2007). High-glycemic-index carbohydrate meals shorten sleep onset. Am. J. Clin. Nutr. 85:426-430. Afaghi, A., H. O’Connor, and C.M. Chow (2008). Acute effects of the very low carbohydrate diet on sleep indices. Nutr. Neurosi. 11:146-154. Bannai, M., N. Kawai, K. Ono, K. Nakahara, and N. Murakami (2012). The effects of glycine on subjective daytime performance in partially sleep-restricted healthy volunteers. Front. Neurol. 3: 61. Buscemi, N., B. Vandermeer, N. Hooton, R. Pandya, L. Tjosvold, L. Hartling, G. Baker, T. P. Klassen, and S. Vohra (2005). The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J. Gen. Intern. Med. 20:1151-1158. Carskadon, M.A., and W.C. Dement (2011). Normal human sleep: an overview. In: M.H. Kryger, T. Roth and W.C. Dement (eds.) Principles and Practice of Sleep Medicine. St Louis: Elsevier, pp. 16-26. Chagoya de Sanchez, V., R. Hernandez-Munoz, J. Suarez, S. Vidrio, L. Yanez, R. Aguilar-Roblero, A. Oksenberg, A. Vega-Gonzalez, L. Villalobos, L. Rosenthal, F. Fernandez-Cancino, R. Drucker-Colin, and M. Diaz-Munoz (1996). Temporal variations of adenosine metabolism in human blood. Chronobiol. Int. 13:163-77. Cubero, J., B. Chanclon, S. Sanchez, M. Rivero, A. B. Rodriguez, and C. Barriga (2009). Improving the quality of infant sleep through the inclusion at supper of cereals enriched with tryptophan, adenosine-5’-phosphate, and uridine-5’- phosphate. Nutr. Neurosci. 12:272-80. Fernandez-San-Martin, M.I., R. Masa-Font, L. Palacios-Soler, P. Sancho-Gomez, C. Calbo-Caldentey, and G. Flores-Mateo (2010). Effectiveness of Valerian on insomnia: a meta-analysis of randomized placebo-controlled trials. Sleep Med. 11:505-511. Fernstrom, J.D., and R.J. Wurtman (1971). Brain serotonin content: physiological dependence on plasma tryptophan levels. Science 173:149-152. Grandner, M.A., D.F. Kripke, N. Naidoo, and R.D. Langer (2010). Relationships among dietary nutrients and subjective sleep, objective sleep, and napping in women. Sleep Med. 11:180-184. Grimmett, A., and M.N. Sillence (2005). Calmatives for the excitable horse: a review of L-tryptophan. Vet. J. 170:24-32. Hartmann, M.K., A.H. Crisp, G. Evans, M.K. Gaitonde, and B.R. Kirkwood (1979). Short-term effects of CHO, fat and protein loads on total tryptophan/tyrosine levels in plasma as related to %REM sleep. Waking Sleeping 3:63-68. Heine, W.E. (1999). The significance of tryptophan in infant nutrition. Adv. Exp. Med. Biol. 467:705-710. Howatson, G., P.G. Bell, J. Tallent, B. Middleton, M.P. McHugh, and J. Ellis (2011). Effect of tart cherry juice (Prunus cerasus) on melatonin levels and enhanced sleep quality. Eur. J. Nutr. 51:909-916. Jalilolghadr, S., A. Afaghi, H. O’Connor, and C.M. Chow (2011). Effect of low and high glycaemic index drink on sleep pattern in children. J. Pak. Med. Assoc. 61:533-536. Jang, H.S., J.Y. Jung, I.S. Jang, K.H. Jang, S.H. Kim, J.H. Ha, K. Suk, and M. G. Lee (2012). L-theanine partially counteracts caffeine-induced sleep disturbances in rats. Pharmacol. Biochem. Behav. 101:217-221. Kwan, R.M., S. Thomas, and M.A. Mir (1986). Effects of a low carbohydrate isoenergetic diet on sleep behavior and pulmonary functions in healthy female adult humans. J. Nutr. 116: 2393-2402. Lacey, J.H., C. Hawkins, and A.H. Crisp (1978). Effects of dietary protein on sleep E.E.G. in normal subjects. Adv. Biosci. 21:245-247. Lindseth, G., P. Lindseth, and M. Thompson (2011). Nutritional effects on sleep. West. J. Nurs. Res. 2011 Aug 4. [Epub ahead of print]. Morin, C.M. and R. Benca (2012). Chronic insomnia. Lancet 379:1129-1141. Orr, W.C., G. Shadid, M.J. Harnish, and S. Elsenbruch (1997). Meal composition and its effect on postprandial sleepiness. Physiol. Behav. 62:709-712. Pigeon, W.R., M. Carr, C. Gorman, and M.L. Perlis (2010). Effects of a tart cherry juice beverage on the sleep of older adults with insomnia: a pilot study. J. Med. Food 13:579-583. Porter, J.M., and J.A. Horne (1981). Bed-time food supplements and sleep: effects of different carbohydrate levels. Electroencephalogr. Clin. Neurophysiol. 51:426-433. Sanchez, C. ., J. Cubero, J. Sanchez, B. Chanclon, M. Rivero, A.B. Rodriguez, and C. Barriga (2009). The possible role of human milk nucleotides as sleep inducers. Nutr. Neurosci. 12:2-8. Saper, C.B., T.E. Scammell, and J. Lu (2005). Hypothalamic regulation of sleep and circadian rhythms. Nature 437:1257-1263. Silber, B.Y. and J.A. Schmitt (2010). Effects of tryptophan loading on human cognition, mood, and sleep. Neurosci. Biobehav. Rev. 34:387-407. Wheatley, D. (2005). Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability. J. Psychopharmacol. 19:414-421. Yamadera, W., K. Inagawa, S. Chiba, M. Bannai, M. Takahashi, and K. Nakayama (2007). Glycine ingestion improves subjective sleep quality in human volunteers, correlating with polysomnographic changes. Sleep Biol. Rhythms 5:126-131. Zammit, G.K., A. Kolevzon, M. Fauci, R. Shindledecker, and S. Ackerman (1995). Postprandial sleep in healthy men. Sleep 18:229-231. ______________________________________________

Sleep in Elite Athletes and Nutritional Interventions to Enhance sleep

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BOTANICALS FOR A BETTER SLEEP

iStock-963914130Imagine waking up fully rested, ready to tackle any challenge and embrace all the pleasures of the world with gratitude. We all know what a good night’s sleep feels like, but how often do we get it? In this hectic, hyper-stimulated, nerve-wracking world, it is challenging to create a sleep routine that our bodies and brains need to function optimally. Good sleep hygiene and use of natural herbs and botanicals can help promote a healthy amount of sleep. The result could mean an improvement in problem solving and work performance, weight management, and prevention of chronic disease such as diabetes, depression and cardiovascular disease. There are multitudes of products and advice in this arena of sleep. An article from 2016 suggested Americans spent over $41 billion on sleep remedies, with an expected increase to upwards of $52 billion by the year 2020. How much sleep do we really need? As you might expect, children require more sleep than adults. The average child needs up to 11 hours of sleep per night, while most adults should get 7-8 hours. According to the Center for Disease Control, the average American gets 6.8 hours. Collectively, we’re not reaching the minimal sleep requirement of 7 hours, and sleep deprivation represents one of the top behaviors deleteriously affecting our overall health. Many factors contribute to this deficit: work schedules, family obligations, and chronic illness or behavioral issues. In most of these cases, our circadian rhythms are completely out of whack. What are some natural remedies or botanicals to help promote sleep? The regulatory body internationally recognized for its comprehensive data on medicinal herbs, the German Commission E, recommends common botanicals (valerian, lavender, lemon balm, and hops) to help support relaxation and promote sleep. There are other popular choices that have sedative qualities, such as passion flower, chamomile, and kava kava. Most of these relaxant botanicals can be found commonly in teas, but they are also available in supplement form. Almost always found in blends, these herbs all have various mechanisms of action, and, therefore, act synergistically when combined. Valerian (Valeriana officinalis) affects sleep by interacting with neurotransmitters GABA, adenosine and serotonin. A two-week randomized controlled trial study comparing the common sleep aid zolpidem (Ambien) with a blend of valerian, passion flower and hops found no statistically significant difference in overall sleep quality. The root or rhizome of this plant is used in either teas or processed into an extract for use in supplements. The extract is standardized to its valerenic acid content, usually containing 0.3-0.8% of the constituent. Doses in supplements are typically 150-600 mg. Use of valerian generally requires about 2 weeks before it appears effective, but studies have been limited to 4-6 weeks, so use beyond that time frame should be approached with caution. Lavender (Lavandula angustifolia) is an extremely popular floral herb found in essential oil form, teas, extracts and in other botanical blends to promote relaxation and relieve stress. Recent research has identified it functions by antagonizing NMDA-receptors and serotonin transporters.  Doses of 80 mg per day lavender in gel cap form for up to 10 weeks have been used in a study where subjects had unspecified anxiety. Both quality and duration of sleep improved in those participants with no sedative side-effects as found in pharmaceutical sleep remedies. Other uses of lavender include 1-2 teaspoons in hot water as a tea daily, or its essential oil diluted in a carrier oil used for massage or in a warm bath. Lavender is generally safe, however it has been known to be toxic if ingested orally. Lemon balm (Melissa officinalis) has ancient roots as an antiviral and stomach-calming agent as well as a treatment for sleep disorders caused by nervousness or tension. Studies have shown the mechanism of action of lemon balm may be related to interactions with GABA-A receptors. Hops (Humulus lupulus), besides having a super fun Latin name and serving as the main ingredient in many beers, is one of the herbs commonly found blended in teas or supplements to produce a calming effect. Researchers have not completely elucidated exactly how hops produces this effect, but it has been shown to bind to serotonin and melatonin receptors. Valerian-hops combination products have been the most widely studied in placebo-controlled, double-blind randomized controlled trials comparing them to benzodiazepine-class sleep medications with varying results. Like lemon balm, evidence for its use as an herbal treatment for relaxation or insomnia has a rich history in tradition. Passionflower (Passiflora incarnata) is another botanical used to address anxiety and insomnia. Researchers have found passionflower functions by increasing levels of GABA, producing a relaxation effect. In a Japanese study from 2017, scientists found passionflower extract modulated the levels of the neurotransmitters and the genetic expression of the related enzymes in vivo and in vitro. This resulted in positive effects on circadian rhythms. Sleep Hygiene Tips Dr. Michael Polsky, a board-certified sleep physician, recommends considering sleep hygiene for improving sleep. Sleep hygiene is a term used to describe how we prepare our minds and bodies for sleep, beginning hours before actual anticipated sleep. In fact, the window of 2-3 hours prior to sleeping turns out to be quite important. Here are some tips for keeping good sleep hygiene:

  • At least 2-3 hours prior to sleep, have a light, balanced dinner and minimize liquids
  • Make a plan to abstain from electronic devices 1-2 hours prior to sleep
  • Do some light activity such as walking or yoga; avoid a hard workout or any activity that is too stimulating
  • Reduce or eliminate caffeine (from coffee, tea, chocolate) in the diet; or no more than 1-2 cups of coffee or tea before lunch
  • Keep a regular sleep schedule, even on weekends

A simple tea recipe Mix up a batch of 2 parts peppermint leaf, 1 part lemon balm, 1 part passionflower, 1 part lavender. Steep one heaping teaspoon in a teacup of hot water for 5 minutes and enjoy as a relaxing beverage. Phenitropic sleep aid link VHP Mix for insomnia _______________________________________________________________

Applications for α-lactalbumin in human nutrition

α-Lactalbumin is a whey protein that constitutes approximately 22% of the proteins in human milk and approximately 3.5% of those in bovine milk. Within the mammary gland, α-lactalbumin plays a central role in milk production as part of the lactose synthase complex required for lactose formation, which drives milk volume. It is an important source of bioactive peptides and essential amino acids, including tryptophan, lysine, branched-chain amino acids, and sulfur-containing amino acids, all of which are crucial for infant nutrition. α-Lactalbumin contributes to infant development, and the commercial availability of α-lactalbumin allows infant formulas to be reformulated to have a reduced protein content. Likewise, because of its physical characteristics, which include water solubility and heat stability, α-lactalbumin has the potential to be added to food products as a supplemental protein. It also has potential as a nutritional supplement to support neurological function and sleep in adults, owing to its unique tryptophan content. Other components of α-lactalbumin that may have usefulness in nutritional supplements include the branched-chain amino acid leucine, which promotes protein accretion in skeletal muscle, and bioactive peptides, which possess prebiotic and antibacterial properties.

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Sleep Facilitates Clearance of Metabolites from the Brain b

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Researchers at Yale published a new study titled “Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital” in Clinical Psychiatry.  In late 2014, Yale began providing ketamine as an off-label therapy on a case-by-case basis for patients who could not participate in research protocols.  The authors observed 54 patients that received IV ketamine infusion for the treatment of severe and treatment-resistant mood disorders such as depression.

“Ketamine is being used as an off-label treatment for depression by an increasing number of providers, yet there is very little long-term data on patients who have received ketamine for more than just a few weeks,” Samuel T. Wilkinson, MD,from the department of psychiatry, Yale School of Medicine and Yale Psychiatric Hospital, told Healio Psychiatry.

The Yale researchers studied the acute and longer-term outcomes in this patient population. Importantly, a subset of patients (n=14) received ketamine on a long-term basis, ranging from 12 to 45 total treatments, over a course of 14 to 126 weeks.  The researchers found no evidence of cognitive decline, increased proclivity to delusions, or emergence of symptoms consistent with cystitis in this subset of long-term ketamine patients.  They also reported that the infusions were generally well-tolerated.

Although this study population was relatively small, limiting the conclusions that can be drawn, this is still an important first step in establishing the long-term safety of ketamine for the treatment of a myriad of diseases that it’s being used to treat.

Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital

Samuel T. Wilkinson, MD; Rachel B. Katz, MD; Mesut Toprak, MD; Ryan Webler, BA; Robert B. Ostroff, MD; and Gerard Sanacora, MD, PhD

J Clin Psychiatry 2018;79(4):17m11731
10.4088/JCP.17m11731

Objective: Ketamine has emerged as a rapid-acting antidepressant, though controversy remains whether sufficient data exist to justify its use outside of research protocols. In October 2014, the authors’ institution began providing ketamine as an off-label therapy on a case-by-case basis for patients unable to participate in research protocols. Here, the participant experience during 29 months of providing ketamine as a clinical treatment for severe and treatment-resistant mood disorders through February 2017 is described.

Methods: Patients were initially treated with a single- or double-infusion protocol (0.5 mg/kg for 40 minutes intravenously) and were later transitioned to a 4-infusion protocol over 2 weeks.

Results: Fifty-four patients received ketamine, with 518 total infusions performed. A subset of 44 patients with mood disorders initiated the 4-infusion protocol, of whom 45.5% responded and 27.3% remitted by the fourth infusion. A subsample (n = 14) received ketamine on a long-term basis, ranging from 12 to 45 total treatments, over a course of 14 to 126 weeks. No evidence was found of cognitive decline, increased proclivity to delusions, or emergence of symptoms consistent with cystitis in this subsample.

Conclusions: In general, ketamine infusions were tolerated well. The response and remission rates in this clinical sample were lower than those observed in some research protocols. The small number of patients who were treated on a maintenance schedule limits the conclusions that can be drawn regarding the long-term safety of ketamine; however, no long-term adverse effects were observed in this sample.

If you are interested in Ketamine therapies for depression, PTSD, pain, anxiety, fibromyalgia…….call 703-844-0184.

Ketamine Fairfax, Va | 703-844-0184

Zip CODES Served by NOVA Health Recovery:

Maryland (MD):
Bethesda 20814 – Bethesda 20816 – Bethesda 20817 – Chevy Chase 20815 – Colesville 20904 – Cabin John 20815 – Glen Echo 20812 – Gaithersburg 20855 – Gaithersburg 20877- Gaithersburg 20878 – Gaithersburg 20879 – Garrett Park 20896 – Kensington 20895 – Montgomery Village 20886 – Olney 20830 – Olney 20832 – Potomac 20854 – Potomac 20859 – Rockville 20850 – Rockville 20852 – Rockville 20853 – Silver Spring 20903 – Silver Spring 20905 – Silver Spring 20906 – Silver Spring 20910 – Takoma Park 20912 – Wheaton 20902
Washington DC:
Crestwood 20011- North Capitol Hill 20002 – Cathedral Heights 20016 – American University Park 20016 – Columbia Heights 20010 – Mount Pleasant 20010 – Downtown 20036 – Dupont Circle 20009 – Logan Circle 20005- Adams Morgan 20009 – Chevy Chase 20015 – Georgetown 20007 – Cleveland Park 20008 – Foggy Bottom 20037 – Rock Creek Park – Woodley Park 20008 – Tenleytown 20016
Northern Virginia:
McLean 22101- McLean 22102 – McLean 22106 – Great Falls 22066 – Arlington 22201 – Arlington 22202 – Arlington 22203 – Arlington 22205 – Falls Church 22041 – Vienna 22181 – Alexandria 22314 – 22308 -22306 -22305 -22304 Fairfax – 20191 – Reston – 22009 – Springfield – 22152 22015 Lorton 22199
Fairfax, Va
2303 – 22307 – 22306 – 22309 – 22308 22311 – 22310 – 22312
22315 -22003 – 20120 – 22015 – 22027 20121 – 22031 – 20124
22030 – 22033 – 22032 – 22035 – 22039 22041 – 22043
22042 – 22046 – 22044 – 22060 – 22066 20151 – 22079 – 20153 – 22101
22102 – 20171 – 20170 – 22124 – 22151 22150 – 22153
22152 – 20191 – 20190 – 22181- 20192 22180 – 20194 – 22182
Woodbridge – 22191 – 22192 -22193 -22194 – 22195
Springfield – 22150 – 22151 -22152-22153-22154-22155 -22156 – 22157 -22158 -22159 -22160 – 22161
Front Royal 22630

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CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

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Ketamine for Depression: A Q&A with Psychiatrist Alexander Papp, MD  << Article link

 

Ketamine for Depression: A Q&A with Psychiatrist Alexander Papp, MD

By Gabrielle Johnston, MPH   |   December 21, 2017

Every year, 15 to 20 million persons are diagnosed and treated for depression, making it the most common type of mental illness in the United States, according to the Centers for Disease Control. For roughly 30 percent of these patients, however, standard treatment options, such as antidepressants and talk therapy, are not effective. But for some, there may be a new option: ketamine, a medication originally developed as an anesthetic drug, but now being used to address treatment-resistant depression. Alexander Papp, MD, psychiatrist at UC San Diego Health, discusses the potential of ketamine as a remedy for depression when other treatments fail.

Alexander Papp

Question: How does ketamine work to reduce depression?

Answer: Ketamine works by quickly increasing the activity of the neurotransmitter glutamate in the frontal cortex of the brain, while also allowing new synapses to form in the same area. The speediness of ketamine in producing an antidepressant effect occurs because this drug bypasses the traditional serotonin route and goes directly to activating glutamate. This is very different from traditional antidepressants, which first increase the activity of serotonin in multiple different areas of the brain, and then ultimately affect glutamate. This process usually takes two to four weeks to take effect, while ketamine yields an almost immediate effect.

Q: What is treatment-resistant depression?

A: Treatment-refractory depression, better known as treatment-resistant depression, is a term used to describe cases of major depressive disorder that do not adequately respond to appropriate courses of at least two antidepressants. In this situation, “responding” to an antidepressant means not only improvement in mood, but experiencing a full disappearance of the majority of the depressive symptoms and a return to normal functioning.

Q: What is ketamine and how is it traditionally used in medicine?

A: Ketamine was originally developed as an anesthetic and an analgesic or pain reliever. Currently, ketamine is approved and labeled by the U.S. Food & Drug Administration (FDA) for both of these uses in the United States.

Q: Are there any adverse effects of ketamine as a treatment? Is this why some consider it to be an “experiential” treatment for depression?

A: As a treatment for depression, ketamine has a few mild adverse effects. These can include a dream-like feeling, blurred or double vision, dizziness, nausea or vomiting and short anxiety reactions after receiving a dose. This treatment is not experimental because this is an FDA-approved drug that is being used for “off-label” or a less common use.  An “off-label” use means that it is administered as a treatment that the FDA did not originally approve. The FDA approves medications only for a certain number of uses, but most medications eventually develop off-label uses due to the clinical experience that develops over time. As an example, the drug Prazosin was approved for the treatment of high blood pressure in 1976 but it is now mostly used for the treatment of nightmares in patients with post-traumatic stress disorder, a use that was not originally approved.

Q: When should a patient ask their doctor about trying ketamine as a treatment for depression?

depression
703-844-0184 | Ketamine infusions in Alexandria, Va 22304 | Mood disorders, fibromyalgia, depression, anxiety

A: You should speak to your doctor when you have tried several antidepressant medications or combinations of medications, taken at the highest dose levels for at least two months, without a return to normal functioning. In these cases, it is also important to have other medical reasons for depression, such as a hormonal imbalance, ruled out as well.

Q: Apart from ketamine, are there any other treatments for this treatment-resistant depression on the horizon?

A: New studies have been published about administering Botox injections into the frown muscles on the forehead to treat depression. Botox is an FDA-approved drug to treat a variety of conditions, ranging from excessive sweating to muscle spasms to cosmetic uses, but its use to treat depression is another example of off-label use.

There are also a variety of other treatments available for this type of depression. Two of the more common options are repetitive transcranial magnetic stimulation and deep brain stimulation. Both of these are FDA-approved and are covered by some insurance plans.

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If you are interested in Ketamine therapies for depression, PTSD, pain, anxiety, fibromyalgia…….call 703-844-0184.

Zip CODES Served by NOVA Health Recovery:

Maryland (MD):
Bethesda 20814 – Bethesda 20816 – Bethesda 20817 – Chevy Chase 20815 – Colesville 20904 – Cabin John 20815 – Glen Echo 20812 – Gaithersburg 20855 – Gaithersburg 20877- Gaithersburg 20878 – Gaithersburg 20879 – Garrett Park 20896 – Kensington 20895 – Montgomery Village 20886 – Olney 20830 – Olney 20832 – Potomac 20854 – Potomac 20859 – Rockville 20850 – Rockville 20852 – Rockville 20853 – Silver Spring 20903 – Silver Spring 20905 – Silver Spring 20906 – Silver Spring 20910 – Takoma Park 20912 – Wheaton 20902
Washington DC:
Crestwood 20011- North Capitol Hill 20002 – Cathedral Heights 20016 – American University Park 20016 – Columbia Heights 20010 – Mount Pleasant 20010 – Downtown 20036 – Dupont Circle 20009 – Logan Circle 20005- Adams Morgan 20009 – Chevy Chase 20015 – Georgetown 20007 – Cleveland Park 20008 – Foggy Bottom 20037 – Rock Creek Park – Woodley Park 20008 – Tenleytown 20016
Northern Virginia:
McLean 22101- McLean 22102 – McLean 22106 – Great Falls 22066 – Arlington 22201 – Arlington 22202 – Arlington 22203 – Arlington 22205 – Falls Church 22041 – Vienna 22181 – Alexandria 22314 – 22308 -22306 -22305 -22304 Fairfax – 20191 – Reston – 22009 – Springfield – 22152 22015 Lorton 22199
Fairfax, Va
2303 – 22307 – 22306 – 22309 – 22308 22311 – 22310 – 22312
22315 -22003 – 20120 – 22015 – 22027 20121 – 22031 – 20124
22030 – 22033 – 22032 – 22035 – 22039 22041 – 22043
22042 – 22046 – 22044 – 22060 – 22066 20151 – 22079 – 20153 – 22101
22102 – 20171 – 20170 – 22124 – 22151 22150 – 22153
22152 – 20191 – 20190 – 22181- 20192 22180 – 20194 – 22182
Woodbridge – 22191 – 22192 -22193 -22194 – 22195
Springfield – 22150 – 22151 -22152-22153-22154-22155 -22156 – 22157 -22158 -22159 -22160 – 22161
Front Royal 22630