ARTICLES

December 2016
Clinical Pearls for Health Care Practitioners
In this edition of our newsletter, we highlight a recently published research paper which focuses on the controversial topic of non-celiac wheat sensitivity.

Standards of practice change slowly in the medical profession, and this topic has remained controversial due to a lack of compelling research.

Those of us more oriented towards the Functional Medicine / Naturopathic paradigm of the spectrum tend to believe that there are many patients who definitely display this reactivity, however published research to corroborate this hypothesis has been lacking.

This paper should go a long way towards supporting this position, however it will take more time and many additional published studies to change the current belief system held by many
Health Care Practitioners that non celiac wheat sensitivity does not exist.

Following is the article.

Regards,

Rob Lamberton

Copyright © 2016 R. V. Lamberton & Associates, All rights reserved.

Gut doi:10.1136/gutjnl-2016-311964

Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease

  1. Melanie Uhde1, Mary Ajamian1, Giacomo Caio2, Roberto De Giorgio2, Alyssa Indart1, Peter H Green1,3, Elizabeth C Verna1, Umberto Volta2, Armin Alaedini1,3,4

+ Author Affiliations

  1. 1Department of Medicine, Columbia University Medical Center, New York, New York, USA
  2. 2Departments of Medical and Surgical Sciences and Digestive System, Centro di Ricerca Biomedica Applicata (C.R.B.A.), University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
  3. 3Celiac Disease Center, Columbia University Medical Center, New York, New York, USA
  4. 4Institute of Human Nutrition, Columbia University Medical Center, New York, New York, USA
  1. Correspondence to Dr Armin Alaedini, Department of Medicine, Columbia University Medical Center, 1130 Saint Nicholas Ave., Room 937; New York, NY 10032, USA; aa819@columbia.edu

Abstract

Objective Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy.

Design Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components.

Results Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals.

Conclusions These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease.

Significance of this study

What is already known on this subject?

  • Some individuals experience a range of symptoms in response to the ingestion of wheat and related cereals, yet lack the characteristic serological or histological markers of coeliac disease.
  • Accurate figures for the population prevalence of this sensitivity are not available, although estimates that put the number at similar to or greater than for coeliac disease are often cited.
  • Despite the increasing interest from the medical community and the general public, the aetiology and mechanism of the associated symptoms are largely unknown and no biomarkers have been identified.

What are the new findings?

  • Reported sensitivity to wheat in the absence of coeliac disease is associated with significantly increased levels of soluble CD14 and lipopolysaccharide-binding protein, as well as antibody reactivity to microbial antigens, indicating systemic immune activation.
  • Affected individuals have significantly elevated levels of fatty acid-binding protein 2 that correlates with the markers of systemic immune activation, suggesting compromised intestinal epithelial barrier integrity.

How might it impact on clinical practice in the foreseeable future?

  • The results demonstrate the presence of objective markers of systemic immune activation and gut epithelial cell damage in individuals who report sensitivity to wheat in the absence of coeliac disease.
  • The data offer a platform for additional research directed at assessing the use of the examined markers for identifying affected individuals and/or monitoring the response to treatment, investigating the underlying mechanism and molecular triggers responsible for the breach of the epithelial barrier, and evaluating novel treatment strategies in affected individuals.

Introduction

Coeliac disease is an autoimmune disorder with genetic, environmental and immunological components. It is characterised by an immune response to ingested wheat gluten and related proteins of rye and barley that leads to inflammation, villous atrophy and crypt hyperplasia in the small intestine. Among the most common manifestations of coeliac disease are abdominal pain, diarrhoea, weight loss, bone disease and anaemia.1 The disease is strongly associated with genes for the specific class II human leucocyte antigens (HLA) DQ2 and DQ8 that are involved in presenting specific immunogenic peptides of gluten proteins to CD4+ T cells in the small intestine.2

Transglutaminase 2 (TG2) appears to be an important player in the disease, both as a deamidating enzyme that can enhance the immunostimulatory effect of gluten and as the target autoantigen in the ensuing immune response.3 The major B-cell responses in patients with coeliac disease target native and deamidated gluten sequences, as well as the TG2 autoantigen. Among these, the IgA anti-TG2 antibody is currently considered the most sensitive and specific serological marker, whereas antibodies to native gluten proteins have low specificity for coeliac disease and have been found to be elevated in a number of other conditions as well.4

Some individuals experience a range of symptoms in response to ingestion of wheat and related cereals, yet lack the characteristic serological, histological or genetic markers of coeliac disease.5–8 The terms non-coeliac gluten sensitivity and non-coeliac wheat sensitivity (NCWS) are generally used to refer to this condition, which is currently understood as the collection of non-specific symptoms in response to ingestion of gluten-containing cereals, and the resolution of such symptoms on removal of those foods from diet in individuals in whom coeliac disease and IgE-mediated wheat allergy have been ruled out.9

The condition is associated with GI symptoms, most commonly including bloating, abdominal pain and diarrhoea, as well as certain extraintestinal symptoms, among which fatigue, headache, anxiety and cognitive difficulties feature prominently.6 Accurate figures for the prevalence of NCWS are not available, although estimates that put the number at similar to or greater than for coeliac disease (1%) are often cited.10 ,11

Despite the commonly used terminology for the condition, the identity of the component(s) of wheat and/or related cereals responsible for triggering the associated symptoms remains uncertain. While recent controlled trials have indicated a prominent role for gluten,7 ,12 non-gluten proteins and fermentable short-chain carbohydrates have also been suggested by some studies to drive aberrant immune responses or to be associated with symptoms.13 ,14

The potential mechanisms behind the onset of symptoms in NCWS remain unknown, and no biomarkers have been identified.10 However, a small number of studies point to increased antibody reactivity to gluten proteins,5 ,15 ,16 moderately raised intraepithelial lymphocyte numbers,5 ,6 ,17 increased intraepithelial and lamina propria eosinophil infiltration5 and enhanced expression of intestinal tight junction protein claudin 4,16 Toll-like receptor 2 (TLR2)16 or interferon gamma (IFNγ),17 suggesting intercellular junction and immune abnormalities in subsets of affected individuals.

Human intestinal epithelial surfaces are colonised by large communities of microorganisms and are in constant contact with an abundance of highly immunogenic microbial products. Compromised intestinal epithelial integrity has been linked to extensive systemic innate and adaptive immune responses that are a consequence of microbial translocation from the lumen into circulation.18

Systemic immune activation in response to microbial translocation is a noted component of HIV infection and IBD.19 In the current study, we investigated (1) whether systemic immune activation in response to translocated microbial products may be a feature of NCWS, (2) whether such systemic immune activation is linked to a compromised intestinal epithelium and (3) whether the systemic immune activation or damage to the epithelium is responsive to the elimination of wheat and related cereals from diet.

Methods

Patients and controls

The study included 80 individuals with NCWS who met the criteria recently proposed by an expert group20 and who were identified using a previously described structured symptom questionnaire21 ,22 (a modified version of the Gastrointestinal Symptom Rating Scale designed to rate symptoms commonly associated with NCWS). All NCWS subjects reported experiencing intestinal and/or extraintestinal symptoms after ingestion of gluten-containing foods, including wheat, rye or barley. The reported symptoms in all subjects improved or disappeared when those foods were withdrawn for a period of 6 months, and recurred when they were re-introduced for a period of up to 1 month.

Individuals were excluded if they were already on a restrictive diet in the past 6 months, if they were positive for the coeliac disease-specific IgA anti-endomysial and/or anti-TG2 autoantibody or for intestinal histological findings characteristic of coeliac disease, or if they were positive for wheat allergy-specific IgE serology or skin prick test. A total of six intestinal biopsies, including two from the duodenal bulb and four from the distal duodenum, were taken from each individual.

Serum samples from all 80 NCWS subjects while on a diet that contained wheat, rye and/or barley were available.

In addition to the above specimens, serum samples were available from 20 of the above NCWS individuals both before and after 6 months of a self-monitored diet free of wheat, rye and barley. These individuals were asked to complete the previously described questionnaire22 before initiating the diet and immediately following its completion. For this study, specific intestinal symptoms (bloating, abdominal pain, diarrhoea, epigastric pain and nausea) and extraintestinal symptoms (fatigue, headache, anxiety, memory and cognitive disturbances, and numbness in arms or legs), selected on the basis of being the most commonly reported symptoms by patients in this population as previously found,6 were considered for analysis.

Symptoms were scored from 0 to 3 as follows: 0=absent, 1=occasionally present, 2=frequently present and 3=always present. A total score, based on the sum of individual symptom scores, was calculated for each individual at the two time points (before and after the diet). The study also included 40 serum samples from patients with biopsy-proven active coeliac disease and 40 serum samples from healthy subjects (both groups on normal non-restrictive diet), recruited as part of the same protocol that included the NCWS individuals.

All cases of coeliac disease were biopsy proven and diagnosed according to established criteria.23 Screening questionnaires were used to evaluate the general health of unaffected controls. Individuals who had a history of liver disease, liver function blood test results (aspartate transaminase, alanine transaminase, alkaline phosphatase, total protein, albumin, globulin and bilirubin) outside the normal range or a recent infection were excluded from all cohorts in the study.

All samples were collected with written informed consent under institutional review board-approved protocols at St. Orsola-Malpighi Hospital, Bologna, Italy. Serum specimens were kept at −80°C to maintain stability. This study was approved by the institutional review board of Columbia University Medical Center.

Assays

Established serological markers of coeliac disease, including IgA antibody to TG2 and IgG and IgA antibodies to deamidated gliadin, were measured as previously described.24 ,25
Serum IgG, IgA and IgM antibodies to native gliadin were measured separately by ELISA as previously described,24 ,26 with the following modification: the secondary antibodies were horseradish peroxidase (HRP)-conjugated anti-human IgG (GE Healthcare), IgA (MP Biomedicals) or IgM (MP Biomedicals). Serum IgG, IgA and IgM antibodies to bacterial flagellin were measured separately using a similar protocol for detecting antibodies to gliadin, with the following modification: plates were coated with a 2 μg/mL solution of highly purified flagellin from Salmonella typhimurium (InvivoGen).

Levels of serum IgG, IgA and IgM endotoxin-core antibodies (EndoCAb) (Hycult Biotech), lipopolysaccharide (LPS)-binding protein (LBP) (Hycult Biotech), soluble CD14 (sCD14) (R&D Systems) and fatty acid-binding protein 2 (FABP2) (R&D Systems) were determined by ELISA, according to the manufacturers’ protocols.

Data analysis

Group differences were analysed by the Kruskal-Wallis one-way analysis of variance, with post hoc testing and correction for multiple comparisons. Correlation analysis was performed using Spearman’s r. A multivariate principal component analysis (PCA) was carried out on the entire dataset to reduce data dimensionality and to assess clustering. The effect of the restrictive diet was assessed by the Wilcoxon matched-pairs test. All p values were two sided, and differences were considered statistically significant at p<0.05. Statistical analyses were performed with Prism 6 (GraphPad) and Minitab 17 (Minitab) software.

Results

Patients and controls

The demographic and clinical characteristics of the study cohorts are included in table 1. Twenty-one (26%) NCWS individuals expressed HLA DQ2 and/or DQ8, a rate not substantially different than in the general population. Small intestine duodenal biopsy showed a normal mucosa (Marsh 0) in 48 (60%) and mild abnormalities, represented by an increased intraepithelial lymphocyte number (Marsh 1) in 32 (40%). In contrast, all patients with coeliac disease in this study expressed HLA DQ2 and/or DQ8 and presented with Marsh 3 grade intestinal histological findings.
View this table:

Table 1
Demographic and clinical characteristics of study cohorts

Markers of coeliac disease and immune reactivity to gluten

The active coeliac disease cohort exhibited significantly elevated IgA antibody reactivity to TG2, as well as IgG and IgA antibody reactivity to deamidated gliadin, when compared with healthy controls (p<0.0001 for each comparison) (figure 1A–C). Patients with coeliac disease also displayed increased IgG and IgA (p<0.0001 for each), but not IgM, antibody reactivity to native gliadin when compared with healthy controls (figure 1D–F).

In the NCWS cohort (while being on a diet that did not restrict the intake of wheat and related cereals), IgG, IgA and IgM antibodies to native gliadin were all significantly higher than in the healthy control group (p<0.0001, p<0.0001 and p=0.018, respectively) (figure 1D–F). However, IgA reactivity to native gliadin in this NCWS cohort was lower than in the coeliac disease group (p=0.015).
There was no association between antibody reactivity to native gliadin and the presence of HLA DQ2 and/or DQ8 genotypes in the NCWS group.

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Figure 1
Markers of coeliac disease and immune reactivity to wheat gluten. Serum levels of (A) IgA antibody to transglutaminase 2 (TG2), (B) IgG antibody to deamidated gliadin, (C) IgA antibody to deamidated gliadin, (D) IgG antibody to native gliadin, (E) IgA antibody to native gliadin and (F) IgM antibody to native gliadin in cohorts of healthy controls, patients with coeliac disease and individuals identified as having non-coeliac wheat sensitivity (NCWS). Horizontal red lines indicate the median for each cohort.

Systemic innate immune activation

Serum levels of both LBP and sCD14 were significantly elevated in individuals with NCWS in comparison with patients with coeliac disease and healthy individuals (p<0.0001 for each comparison) (figure 2A, B). There was a highly significant correlation between serum LBP and sCD14 (r=0.657, p<0.0001) (see online supplementary figure S1). Neither LBP nor sCD14 was found to be significantly elevated in patients with coeliac disease when compared with healthy controls.

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Figure 2
Markers of systemic immune response to microbial components. Serum levels of (A) lipopolysaccharide-binding protein (LBP), (B) soluble CD14 (sCD14), (C) endotoxin-core antibodies (EndoCAb) IgG, (D) EndoCAb IgM, (E) IgG antibody to flagellin and (F) IgM antibody to flagellin in cohorts of healthy controls, patients with coeliac disease and individuals with non-coeliac wheat sensitivity (NCWS). Horizontal red lines indicate the median for each cohort.

Supplementary figures

[gutjnl-2016-311964supp_figures.pdf]

B-cell response to microbial antigens

When compared with the healthy control and coeliac disease cohorts, the NCWS group had significantly higher levels of EndoCAb IgM (p<0.0001 and p=0.028, respectively) (figure 2D), but not IgG or IgA (see figure 2C and online supplementary figure S2A). In contrast to the NCWS cohort, the coeliac disease group had higher levels of EndoCAb IgA when compared with the NCWS and healthy control groups (p=0.021 and p=0.032, respectively) (see online supplementary figure S2A), but not IgG or IgM (figure 2C, D).

Furthermore, the levels of IgG and IgM antibodies to flagellin were significantly elevated in the NCWS cohort when compared with the healthy control group (p=0.001 and p=0.009, respectively) (figure 2E, F). These antibodies were not significantly elevated in the coeliac disease cohort, although there was a trend towards higher IgA reactivity to flagellin when compared with healthy controls (p=0.059) (see online supplementary figure S2B). The increased IgM antibody response to flagellin correlated with the elevated EndoCAb IgM in the NCWS cohort (r=0.386, p<0.0001) (see online supplementary figure S3).

Systemic immune activation is associated with increased intestinal epithelial cell damage

In comparison with the healthy control group, serum concentrations of FABP2, a marker of intestinal epithelial cell damage, were significantly elevated in the NCWS cohort, as well as in the coeliac disease group (p<0.0001 for each) (figure 3A). In addition, the FABP2 concentrations in the NCWS cohort correlated with levels of LBP (r=0.360, p=0.001) and sCD14 (r=0.461, p<0.0001) (figure 3B, C).

The FABP2 concentrations in the NCWS group also correlated with EndoCAb IgM (r=0.305, p=0.003) and anti-flagellin IgM antibody reactivity (r=0.239, p=0.033) in the NCWS cohort (see online supplementary figure S4A, B). In the coeliac disease cohort, FABP2 concentrations correlated with the levels of IgA antibody to TG2 (r=0.559, p<0.0001) (see online supplementary figure S5).

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Figure 3
Intestinal epithelial cell damage and correlation with systemic immune activation. (A) Serum levels of fatty acid-binding protein 2 (FABP2) in cohorts of healthy controls, patients with coeliac disease and individuals identified as having non-coeliac wheat sensitivity (NCWS). (B and C) Correlation of serum levels of FABP2 with lipopolysaccharide-binding protein (LBP) (B) and soluble CD14 (sCD14) (C) in individuals with NCWS. Horizontal red lines indicate the median for each cohort.

Multivariate analysis of dataset

PCA was used to assess similarities and differences between the subjects in the three cohorts based on the generated data and to determine whether they can be grouped. Most of the variability in the data could be explained by the first two components (54%). The score plot of the first and second components for the entire dataset demonstrated the clustering of the healthy control, coeliac disease and NCWS subjects into three discernible groups, with some outliers (figure 4).

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Figure 4
Principal component analysis (PCA) score plot for the complete dataset of serological markers (anti-transglutaminase 2 (anti-TG2) IgA; anti-deamidated gliadin IgG and IgA; anti-gliadin IgG, IgA and IgM; lipopolysaccharide-binding protein (LBP); soluble CD14 (sCD14); endotoxin-core antibodies (EndoCAb) IgG, IgA and IgM; anti-flagellin IgG, IgA and IgM; and fatty acid-binding protein 2 (FABP2)) measured in healthy controls, patients with coeliac disease and individuals with non-coeliac wheat sensitivity (NCWS). Subjects are plotted in two dimensions using the first and second principal components (PC1 and PC2).

Systemic immune activation and intestinal epithelial cell damage respond to dietary restriction

Levels of the above markers of immune activation and gut epithelial cell damage were also measured in 20 of the above NCWS subjects before and 6 months after initiation of a diet free of wheat, rye and barley. All individuals reported symptom improvement at the end of 6 months, which was reflected in a significant reduction in both the intestinal and extraintestinal composite symptom scores (p<0.0001 for each) (figure 5A, B), accompanied by a decline in IgG, IgA and IgM anti-gliadin antibodies (p<0.0001, p=0.002 and p=0.004, respectively) (figure 5C–E). In conjunction with this, we found a statistically significant reduction in the serum levels of LBP (p=0.0002), sCD14 (p=0.0006), EndoCAb IgM (p=0.006), anti-flagellin IgG and IgM antibodies (p=0.002 and p=0.003, respectively) and FABP2 (p=0.003) after the completion of the diet (figure 6A–F). The magnitude of change in the measured biological markers did not correlate significantly with that for the symptom scores.

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Figure 5
Symptoms and anti-gliadin antibody reactivity in response to the restrictive diet. (A and B) Composite scores for intestinal symptoms (bloating, abdominal pain, diarrhoea, epigastric pain and nausea) and extraintestinal symptoms (fatigue, headache, anxiety, memory and/or cognitive disturbances, and numbness in arms and/or legs) before and after 6 months of a diet free of wheat, rye and barley in a cohort of 20 patients with non-coeliac wheat sensitivity (NCWS). (C–E) Levels of IgG, IgA and IgM antibody to gliadin proteins before and 6 months after starting the diet in the NCWS cohort. Each individual is represented by a dot and the two points corresponding to the same individual are connected by a line. Each box indicates the 25th–75th percentiles of distribution, with the horizontal line inside the box representing the median.

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Figure 6
Markers of intestinal epithelial cell damage and systemic immune activation in response to the restrictive diet. (A–F) Levels of lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14), endotoxin-core antibodies (EndoCAb) IgM, anti-flagellin IgG, anti-flagellin IgM and fatty acid-binding protein 2 (FABP2) before and after 6 months of a diet free of wheat, rye and barley in the cohort of 20 patients with non-coeliac wheat sensitivity (NCWS). Each individual is represented by a dot and the two points corresponding to the same individual are connected by a line. Each box indicates the 25th–75th percentiles of distribution, with the horizontal line inside the box representing the median.

Discussion

As expected, the cohort of individuals with sensitivity to wheat in the absence of coeliac disease did not exhibit significantly elevated antibody responses to TG2 or deamidated gliadin sequences. This indicates that in contrast to coeliac disease, the observed humoral immune response to gluten in NCWS is independent of TG2 enzymatic activity and HLA-DQ2/DQ8, and is likely to target certain epitopes that are distinct from those in coeliac disease. We hypothesised that the enhanced antibody response to native gliadin in NCWS individuals, particularly IgG and IgM isotypes, may be a consequence of ongoing intestinal epithelial barrier defects.

If so, such defects might also give rise to an inadequate regulation of the interaction between the gut microbiota and systemic circulation, resulting in peripheral immune activation. To examine this, we measured the levels of LBP and sCD14 as indicators of the translocation of microbial products, particularly LPS, across the epithelial barrier. Translocated circulating LPS can result in the rapid secretion of LBP by GI and hepatic epithelial cells, as well as sCD14 by CD14+monocytes/macrophages.19 sCD14 binds LPS in the presence of LBP to activate TLR4.27 We found significantly elevated serum levels of both LBP and sCD14 in individuals with NCWS in comparison with patients with coeliac disease and healthy controls. The high degree of correlation between serum LBP and sCD14 suggested that these molecules are concurrently expressed in response to the stimulus in NCWS individuals.

We also quantified serum levels of antibody to LPS core oligosaccharide, or EndoCAb, which is known to modulate in response to bacterial endotoxin in circulation.28 As they are involved in the neutralisation of circulating endotoxin, EndoCAb immunoglobulins are typically depleted in response to an acute LPS exposure, but eventually rise due to the B-cell anamnestic response.19 Individuals in the NCWS cohort exhibited increased levels of EndoCAb IgM.

To demonstrate that the systemic immune response in individuals identified as having NCWS would not be limited to only LPS if driven by translocated microbial products, we also measured serum levels of antibody to flagellin, the principal substituent protein of the flagellum in Gram-positive and negative bacteria. We found that levels of IgG and IgM antibodies to flagellin were significantly elevated in the NCWS cohort. Considering that no individuals in this study had evidence of infection, these observations are suggestive of a translocation of microbial products from the GI tract that contributes to the observed innate and adaptive immune activation in the NCWS cohort.

Circulating bacterial components, such as LPS and flagellin, bind to their respective TLRs on various cells, including macrophages and dendritic cells, which results in signalling through the myeloid differentiation factor 88 (MyD88) adaptor protein.27

Ultimately, MyD88 signalling leads to the activation of transcription factor nuclear factor-κB and increased expression of various proinflammatory cytokines that can exert deleterious systemic effects.19 ,29 A systemic innate immune activation model would be consistent with the generally rapid onset of reported symptoms in NCWS.6 In addition, circulating microbial products can bind to TLRs on other cells to trigger a more localised inflammatory response. For example, LPS binds directly to TLR4 on the luminal surface of brain blood vessels, resulting in local cytokine secretion in the brain that has been shown to activate the microglia to displace inhibitory synapses.30

In HIV infection, where the presence of microbial translocation is linked to intestinal epithelial damage, increased systemic immune activation in response to bacterial antigens is associated with cognitive deficits.31 Such a pathway might contribute to some of the neurocognitive symptoms experienced by NCWS individuals.
Subsequently, we considered whether the observed systemic immune activation in response to microbial products in individuals with NCWS may be linked to increased intestinal enterocyte damage and turnover rate.

FABP2 is a cytosolic protein specific to intestinal epithelial cells that is rapidly released into systemic circulation after cellular damage.32 Alterations in circulating FABP2 concentration, reflecting epithelial cell loss and changes in enterocyte turnover rate, are useful for identifying acute intestinal injury.32–35 Elevated circulating FABP2 has been shown to be associated with increasing degrees of villous atrophy in coeliac disease,36 and with microbial translocation in HIV37 that is in turn linked to damaged intestinal epithelial barrier integrity.18

Similar to the patients with coeliac disease, the NCWS individuals in this study were found to have raised circulating FABP2 levels, indicating increased intestinal epithelial cell damage. FABP2 concentrations in the NCWS cohort correlated strongly with levels of LBP and sCD14, suggesting a link between the intestinal epithelial cell damage and the acute systemic immune activation in response to translocated microbial products.

The FABP2 concentrations in the NCWS group also correlated with IgM antibody reactivity towards microbial antigens, though less strongly in comparison with LBP and sCD14 responses, as might be expected for a systemic antibody response. In the coeliac disease cohort, FABP2 concentrations correlated with the increased IgA antibody to TG2, confirming the existence of a close relationship between the mucosal autoimmune response and the intestinal damage in this disease.

In contrast to coeliac disease, however, investigations of small intestine biopsies in NCWS subjects in this and other studies have not found villous atrophy or mucosal architectural abnormalities,5 ,6 ,21 ,38 even if significant inflammatory changes are seen.5 One possible explanation for this could be that the epithelial damage associated with NCWS is in regions other than the duodenum from where biopsies are generally taken in such individuals.

This would be plausible because FABP2 is expressed primarily by the epithelial cells of the jejunum,33 ,39 which may point to this region of the small intestine as a potential primary site of mucosal damage in NCWS. Different sections of the GI tract have unique cellular, structural and immunological features that make them vulnerable to specific insults.40 Another possibility is that the epithelial changes associated with NCWS might be more subtle in comparison with coeliac disease, without overt remodelling of the mucosa.

For example, tumour necrosis factor (TNFα)-mediated enhancement of enterocyte loss has been shown to cause mucosal barrier dysfunction and physical gaps in the epithelium that require confocal and scanning electron microscopy for visualisation.41
On the other hand, despite the established extensive villous damage associated with coeliac disease, neither LBP nor sCD14 levels were found to be significantly elevated in the coeliac disease group, thus standing in stark contrast to the NCWS cohort.

In addition, among the immunoglobulin responses to microbial antigens, only IgA antibodies appeared to be increased in coeliac disease. These data suggest that there is an effective mechanism for the neutralisation of microbial products that may cross into the lamina propria in most cases of coeliac disease, possibly in part via the localised IgA response and mucosal phagocytic cells.

These mechanisms are known to be essential for the immune surveillance of luminal antigens and the elimination of microbial products that cross the epithelial barrier, thereby reducing the likelihood of their translocation into the submucosa and access to blood vessels.19 Such mucosal immune responses may be lacking or inadequate in individuals with NCWS. Instead, what we observed were enhanced IgM responses to gliadin, LPS and flagellin in the NCWS cohort, which clearly contrasted with the coeliac disease group. In humans, IgM memory B cells are present in the peripheral blood and contribute to the expression of IgM antibodies to a diverse variety of antigens, offering a first line of defence against potential pathogens.42

Exposure to unmethylated CpG sequences, which are abundant in the bacterial and viral genomes, can result in TLR9-dependent proliferation and differentiation of these B cells, independent of direct interaction with their respective antigens or T-cell involvement.43 Acute microbial translocation from the gut, as the data from our study suggest, would be expected to enhance the secretion of IgM antibodies in the periphery via this pathway.

These IgM B cells would be additionally stimulated on encounter with specific antigens, such as the translocated microbial components or gliadin sequences, and may contribute to the observed IgM antibody responses.43 ,44 Recognition and agglutination of antigens by IgM and IgG antibodies can result in the activation of the classical complement pathway and Fc receptor-mediated endocytosis by macrophages,45 further contributing to the ongoing systemic immune response.

The hallmark of NCWS is the onset of intestinal and/or extraintestinal symptoms on ingestion of gluten-containing foods, that is, wheat, rye and barley, and the alleviation of symptoms on their withdrawal from diet. To determine whether the patient-reported symptom resolution on the elimination of these foods would be associated with the amelioration of intestinal epithelial cell damage and a reduction in microbial translocation and systemic immune activation, we examined the above markers in a subset of NCWS subjects before and after a diet that excluded wheat and related cereals.

The results indicated a significant decline in the markers of immune activation and gut epithelial cell damage, in conjunction with the improvement of symptoms. However, the magnitude of change in the measured biological markers did not correlate significantly with that for the symptom scores. This appears to be similar to observations in patients with coeliac disease, where symptoms are known to be a poor predictor of disease activity and associated biomarkers.46 ,47

A limitation of this portion of the study was the absence of a healthy control group to assess the potential impact of the dietary restriction in unaffected individuals.

In summary, the results of this study on individuals with sensitivity to wheat in the absence of coeliac disease demonstrate (1) significantly increased serum levels of sCD14 and LBP, as well as antibody reactivity to microbial antigens, indicating systemic immune activation; (2) an elevated expression of FABP2 that correlates with the systemic immune responses to bacterial products, suggesting compromised intestinal epithelial barrier integrity and increased microbial translocation; and (3) a significant change towards normalisation in the levels of the immune activation markers, as well as FABP2 expression, in response to the restrictive diet, which is associated with improvement in symptoms.

Our data establish the presence of objective markers of systemic immune activation and epithelial cell damage in the affected individuals. The results of the multivariate data analysis suggest that a selected panel of these may have use for identifying patients with NCWS or patient subsets in the future. It is important to emphasise that this study does not address the potential mechanism or molecular trigger(s) responsible for driving the presumed loss of epithelial barrier integrity and microbial translocation. Further research is needed to investigate the mechanism responsible for the intestinal damage and breach of the epithelial barrier, assess the potential use of the identified immune markers for the diagnosis of affected individuals and/or monitoring the response to specific treatment strategies, and examine potential therapies to counter epithelial cell damage and systemic immune activation in affected individuals.

Acknowledgments

The authors thank Dr Timothy C Wang (Columbia University) and Dr Donald D Kasarda (US Department of Agriculture) for the critical review and discussion of the manuscript. The authors are also grateful to Dr Benjamin Lebwohl and Dr Daniel E Freedberg (Columbia University) for insightful discussions and input during the course of the study.

Footnotes

  • Contributors AA had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. AA: study concept and design. MU, MA, GC, RDG, AI, ECV, PHG, UV and AA: contribution to study design. MU, MA, GC, RDG, AI and UV: acquisition of data. MU, MA, GC, RDG, AI, ECV, PHG, UV and AA: analysis and interpretation of data. MU and AA: drafting of the manuscript. MU, MA, GC, RDG, PHG, ECV, UV and AA: critical revision of the manuscript for important intellectual content. MU and AA: statistical analysis. GC, RDG, ECV, PHG, UV and AA: administrative, technical or material support. AA: obtained funding. AA: study supervision.
  • Funding This study was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR000040 (to AA) and The Stanley Medical Research Institute through grant number 08R-2061 (to AA). Additional support was provided by the Italian Ministry of University, Research and Education through grant number 2009MFSXNZ_002 (to RDG), the Italian Ministry of Public Health through Ricerca Finalizzata Regione Emilia Romagna-2009 (to RDG), and funds from the University of Bologna. The funding agencies had no role in the design and conduct of the study; in the collection, analysis and interpretation of the data; or in the preparation, review or approval of the manuscript.
  • Competing interests None declared.
  • Patient consent Obtained.
  • Ethics approval Institutional Review Board of Columbia University Medical Center.
  • Provenance and peer review Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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September 15, 2016
Brian Wagner – NHP consulting

Proposed NHP Changes in Canada: Bad Idea?

This is a topic of high interest to me, as it speaks to the free market access of health products in Canada. On Friday, Health Canada put out a consultation paper outlining their wish list of proposed regulatory changes in Canada. From what I can tell, no one likes this proposal.

The proposal came out of left field. I am told that Health Canada had high level briefings with trade associations (including CHFA and CHPC), but this was not what I would call a “consultation”.

In a nutshell, the proposal is seeking to combine the regulatory scheme for cosmetics, natural health products and OTC drugs, all into one system. Their reasoning is that, if products of the same inherent risk are making the same claims, they should be regulated in the same way. So far, not an unreasonable premise.

Manufacturing standards for quality would be required for all such self-care products (a new term), including cosmetics. No changes were discussed for GMP manufacturing standards for nhp’s, neither for drugs.

Cosmetics would be blended into the current nhp regulatory oversight, but it’s largely unclear how this would affect cosmetics. My take-away is that cosmetics would have to be notified (same as they are today), but would likely have to declare ingredients by exact concentration and such ingredients would have to be acceptable against a certain list. So, not only a negative list (like the current Hot List), but also against a positive list (like the NHP Ingredients Database). They may also require some kind of “tracking number” on the label to identify that they have been in fact notified. This suggests a pre-market notification process to me.

OTC drugs, from the proposal, appear unchanged. From what I read, OTC drugs would remain at their current licensing standards, however some lower risk OTC drugs may have a lower evidence burden for efficacy depending on the claim being made. For example, a very safe non-natural active ingredient claiming to treat acne, but which does not have a labelling standard or NNHPD monograph, may come to market with less evidence. But again, this is not discussed specifically in their proposal.

Natural health products (nhp’s), on the other hand, are where the real impact would be seen. Most of their proposal has to do with nhp regulation, and they are proposing to divide nhp’s into three “categories” – low risk, medium risk, and high risk. Sounds familiar, but it gets more intricate. Remember, the devil is always in the details – and if we are to learn anything from the 2004-2010 licensing crisis, it is always in the details.

First, their major proposed change is to redefine a health claim. As of Friday, their proposal is to effectively treat all non-restorative structure-function claims, non-specific health claims, and generalized health claims, as simply “claims” – not “health claims”. If this sounds familiar it should; this is the model in the USA under DSHEA. Basically, the proposal is that Health Canada would not review/license such claims, and their only oversight of claims would be what they are (now) calling “health claims” – claims for the treatment, prevention or diagnosis of diseases/conditions. Basically, a health claim is, under this proposal, a statement for improving something that is abnormal, diseased or unhealthy. A product that claims to simply “promote bone health” isn’t making a health claim, under this new interpretation.

This is a huge reversal of policy. Of the 100,000 or so nhp’s licensed on the market today, the vast majority of them are not making “health claims” in this new definition. Apparently they’re just making “claims”, and Health Canada doesn’t think they’re real. Not real enough to license.

In the past, Health Canada always struggled with this. After all, Health Canada in 2003-2004 decided to not create a third category of products and treat nhp’s as a subclass of drugs (according to the Food and Drugs Act). In theFood and Drugs Act, a drug is represented/sold for use in “restoring, correcting or modifying organic functions in human beings” as well as treating/preventing diseases/disorders. In theory, a drug could therefore be a product that simply “modifies an organic function”.

The Natural Health Products Directorate (NHPD, now called NNHPD) in 2004-2006 greatly struggled with the definition of a health claim. They were hesitant to license structure-function claims that were non-restorative, and they had a terrible time with so-called generalized health claims (or non-specific health claims) such as “promotes bone health”. It is my opinion that the licensing crisis of 2004-2010 – when the NHPD had a backlog of over 12,000 applications and made no progress through it – was absolutely based on their inability to define what constitutes a health claim.

The NHPD, under Scott Sawler, in 2009-2010 proposed sweeping changes to the regulation of natural health products, and started allowing simple and non-specific claims based on a fair level of evidence. This cleaned up the backlog, and allowed almost every product on the market to achieve a licence (called a Natural Product Number).

For my industry colleagues who fought this good fight beside me, we fought this battle alongside the CHFA and lobbied extensively to “save our natural health products”. Our message was that we are not drugs – and can’t be treated as drugs. We don’t want to be drugs. We want the ability to make claims, to come to market when there is no safety risk, and let consumers decide for themselves.

The other important proposal here is that, should a product make a claim that is not a health claim, they have to include some kind of disclaimer on the label. Something similar to what we see in the USA, I would imagine (e.g., “Health Canada has not reviewed the statements made about …”). Basically Health Canada is saying that they don’t think consumers understand these claims, and/or they don’t feel there is any real scientific evidence to substantiate them. The claim “Promotes bone health” in their minds is not something they want to be a part of. They want consumers to decide on their own – do their own research, they say – and their way of telling consumers to do this, is to put a disclaimer on the label.

Before I get into more about claims, let me also put out their other proposals, which are equally troublesome. First, they want to introduce cost recovery fees finally – we all knew this was coming, and probably it will be hard to stop them from doing this. So, today there are no review fees for getting an NPN – but in the near future it could cost $1000 to $2000 per product – or more, depending if it’s medium or high risk. An OTC DIN fee is around $1700 per SKU.

Perhaps the most troubling, though, is the re-emergence of inspectorate powers. Health Canada wants the legal right to force a company to recall an nhp, and to have higher powers of penalty and inspection. If this sounds familiar, it should. In 2008 the government announced Bill C-51 which would do just this. There was such a tremendous uproar from the health products industry, that they backed away. At the time, Minister Tony Clement came under intense heat over the bill (interviewed for Alive Magazine here). CHFA helped organize a campaign. So, here we go again. Perhaps the Liberals don’t remember the old bill.

If It Ain’t Broke

There’s an old saying, “if it ain’t broke, don’t fix it”. Apparently Health Canada thinks something is broken and wants to fix it. So, what’s broken?

Health Canada says they did a survey in April this year from 2,500 Canadian consumers asking about how “informed” they feel when purchasing nhp’s, cosmetics and OTC drugs. As stated in the consultation document (though I have not seen the actual survey results), only 19% considered themselves well informed when purchasing nhp’s, compared to 29% for cosmetics and a whopping 37% for OTC drugs. Health Canada did not outright say this, but they should have – it really doesn’t seem to matter what category of self-care product it is, Canadians don’t feel well informed. Is 37% for OTC drugs staggeringly low? So, basically, one in 3 Canadians buying cold medicine don’t feel well informed? And only one in five feel well informed about natural health products?

But again, this is not something that’s broken. Canadians, like most people in the world, don’t read labels. But that has to be true for toys, a bed for my kid I bought from Ikea, or the toaster that absolutely warns me not to stick my fingers in the bread holes. Consumers are confronted with massive amounts of information every day – and, frankly, it’s tiring to read. I would say we’re all sick of reading.

I have an issue with how Health Canada put out their consultation paper. They say they want feedback from stakeholders (including consumers), but they’re not presenting us with the survey results. They didn’t even present us with the statistical analysis. Was there a statistically significant difference in the group of responses for the 19%, 29% and 37%? Were there between-group differences? We don’t know. They didn’t tell us.

29% for cosmetics and 37% for OTC drugs. Let’s assume there was no statistically significant difference (i.e., no meaningful difference) between these, which means Canadians feel pretty much just as informed about buying cosmetics as they do about buying OTC drugs. Why is that? OTC drugs come with a hefty amount of literature with the product. Despite this, Canadians feel just as informed?

They don’t read labels. Period. But please, Health Canada, treat us like intelligent people and provide us with the data and statistical analysis to make a real decision on your survey.

Even if the results were statistically significant, why would this be a problem? If only 19% of Canadians feel “well informed” when buying an nhp, what’s the harm? I mean, how much do any of us really know about the products we buy? Are we putting ourselves in danger? Is that multivitamin going to give me cancer? What’s the risk in Canadians making uninformed decisions when purchasing nhp’s? After all, Health Canada has assessed the safety at minimum.

Last week I bought a box of pens and none of them worked. The label didn’t stop me from buying them, and I’m out a few bucks. Should Health Canada protect me from making bad purchases?

Many of the claims currently on nhp products are hard to gauge efficacy anyways. “Promotes cardiovascular health” is a great claim – but hard to prove based on the level of data Health Canada would want for a drug. But where’s the harm?

Health literacy has, time and time again, proven to be a stumbling block for Health Canada. Their only tools for regulating health products are (1) allowing/prohibiting them; or (2) dictating what appears on the label. Canadians likely expect all products allowed on the market to be safe (right or wrong), but if their only other tool it seems is labelling.

Does changing the label content really improve health literacy? If a product had a claim “promotes bone health” and then also a disclaimer that the claim wasn’t reviewed by Health Canada – would this improve how “informed” they were about making the purchase? I am saying no, it makes no improvement. In fact, I am saying that it would make it worse. Now there’s a claim that can be made without any review and Health Canada is saying they haven’t reviewed it. Sounds worse. And the disclaimer would be in both French and English, I would imagine, so here’s even more crowded label. Crowded labels are probably read even less.

Surely Health Canada has more creative ideas on improving health literacy for self-care products, other than slapping a disclaimer on the label. If Canadians are ill-informed about products they are buying, is this the government’s role to improve this? Again, what’s the harm? If a consumer decides not to read the label or do their own research – and is much they can find out  themselves should they desire – shouldn’t this be their choice? Should our government protect us from our own ignorance and poor decision making?

We’ve Been Here Before

The truth is, we fought this battle years ago and thought we found a cease fire. The NHP Regulations and NNHPD guidance documents as they are today, do in fact allow for most products to come to market with some kinds of claims suggesting to the consumer what the product is for. Overall it’s fairly good.

But we’ve been here before. We fought hard to have the kind of regulatory oversight we have today, and in my opinion the system is world class. No other country in the world – and I know, because we consult for all major markets – has the kind of system that Canada has. We are a world class regulator. With the exception of lack of on-site audits for quality standards (which I would welcome), the system works.

Moving to a DSHEA kind of approach is a step backwards. If anything, consumers will be even more confused with the disclaimers, and with products suddenly not having licences. Consumer confidence in health products in general would diminish. So suddenly the government feels these claims aren’t legitimate? – even though they approved them in the past?

I had thought this issue would be behind us, but this is a powerful reminder that as an industry we need to keep watch.

Gaps and Holes

In addition to the proposal being unjustified, as detailed above, there are glaring holes in their proposal. For example, would low-risk products need to be imported by a site licence holder? Or could anyone import them for resale? What happens to the NPN that was obtained legitimately in the past? – would it suddenly be worthless?

What if a manufacturer wanted to make a real health claim on a so-called low-risk product? For example, a prevention claim for a calcium product? The proposal suggests they wouldn’t allow this. No health claims for low-risk products.

Or what happens if a medium risk formulation (risk is based on the composition, remember) wants to make a treatment claim? Or what if a high-risk formulation (based on composition) wants to make a softer claim?

What type of “science” would they suddenly require for the high-risk category of products? For example, safety studies on the finished product (similar to drugs)? Product-basd efficacy? Double blind randomized controlled trials for a claim such as “Prevents gingivitis”?

In the licensing crisis of 2004-2010, the major problem was the standards of evidence for efficacy (making health claims). This proposal doesn’t mention what the standards would be. However, I would guess they would be closer to the OTC drug standard, which is quite high. So now, if you want to make a real health claim, you’re pretty much coming to market with an OTC drug.

Moving Forward

Based on my talks with clients and industry associations, this proposal will die almost as soon as it started. It was so poorly conceived, with such short-sightedness (and forgetfulness of past mistakes), that backlash will be strong. Larger pharma companies I know from fact are also not pleased with this – and the major cosmetic companies are dead against this.

If we see any kind of regulatory change, I am guessing the only aspects of this that will survive are introducing review fees, cosmetic notifications being managed by NNPHD (new name now? NNCHPD?) but remaining largely the same, and perhaps a greater emphasis on quality inspections at the manufacturing level (which we’re already seeing). Otherwise, there is nothing else here that the industry will accept.

If the industry takes a back seat through all of this and does not act, the following could happen:

  1. Some 80% of marketed products (and almost all cosmetics) would need to change their labels, especially by adding a disclaimer about non-licensed claims.
  2. Products already with an NPN but now deemed high risk, will have to renew their NPN’s under the new framework. Likely they will do this by allowing them to keep their NPN’s but making the NPN’s expire, and the new standards would apply at renewal.
  3. Many products would simply disappear from the market, either from ineligibility under the new standards for high-risk products, or else suppliers would lose confidence in the future of the market.
April 15, 2016

                                                                                                                                              Clinical Pearls for Health Care Professionals

Functional Medicine Updates

 Betaine, also known by the name Trimethylglycine (TMG) is well known and utilized within the Practitioner community for its important and profound effects on methylation and Homocysteine levels.

It is also known for its impact on mood and depression due to the fact when TMG helps to break down Homocysteine into Methionine, and a byproduct of this conversion is SAMe –  S-adenosylmethionine, which is known to be effective in the treatment of depression, schizophrenia, demyelination diseases, liver disease, dementia, arthritis, and other conditions.

Recently, the Journal of Neurochemistry reported the brain levels of SAMe in Alzheimer’s patients are severely decreased.

Perhaps not as well-known is TMG’s significant impact on inflammation, which has significant potential anti-aging effects.
Following is an article from Life-Enhancement Magazine which documents this anti-inflammatory modulation.

Also we have included an article written by Nicholas Rupcich, PhD (McMaster – Biological Chemistry).

But first let’s review some of the more well-known potential benefits of TMG supplementation:

From Dr. Wilson’s article on TMG:

FUNCTIONS OF TMG

A powerful and safe methyl donor.  TMG easily donates three methyl groups to the body.  Methyl groups (CH3) are required in millions of biochemical reactions in human and animal bodies.  Here are just a few of the best studied examples:

  • Lowering homocysteine.
  • Helping with liver detoxification.
  • Alleviating depression.
  • Reducing the chances of diabetes.
  • Avoiding genetic problems.

TMG has an overall parasympathetic effect.  TMG seems to help restore balance to the autonomic nervous system, especially in those who are following a complete nutritional balancing program.  This may be one of its most important benefits.

TMG is good for those with an MTHFR defect
Anti-oxidant and anti-inflammatory effects.
Profound effects on the brain, digestion and other body systems.

Elevated Homocysteine Levels increase risk factors for:

  • Cardiovascular disease
  • Heart Attack, Stroke
  • Neural Tube Defects
  • Cancer
  • Liver Disease
  • Depression
  • Peripheral Neuropathy

Taken with permission from “Your Life Depends on it! Understanding Homocysteine Methylation and Your Health”, Paul Frankel, Ph.D., published with Specialty Laboratories, Santa Monica, CA.

BIOLOGICAL BENEFITS OF TMG (Trimethylglycine)

Betaine /TMG (not to be confused with Betaine HCL) works along with Vitamin B6, folic acid and Vitamin B12 to augment the formation of SAMe, an amino acid in the brain. Amino acids are proteins.

It helps with the Methylation process which is necessary for life

TMG (Betaine Anhydrous) is a primary methyl donor with the following applications in human nutrition: 

  • By raising level of beneficial SAMe (S-Adenosyl-Methionine).
  • Body building:In the animal husbandry field, TMG is used to decrease fat and increase meat yield. While human studies have just started, a 200 pound individual with 20% body fat can expect to lose as much as 5 pounds of fat and gain as much as 12 pounds of muscle.
  • Cardiac protection:Conversion of homocysteine to Methionine. General Health Preventative: As part of a formula for maintaining good health or disease prevention.
  • Glutathione Elevation:In several different studies, TMG has been shown to increase hepatic Glutathione, the body’s most important antioxidant.
  • Homocysteine Lowering:Specific for that purpose. The supplement of choice for lowering homocystenuria
  • Liver Disorders:As a part of liver-healing and protection formulas. Increases SAM levels in the liver, enables the liver to metabolize fat and protect against many challenges such as alcohol induced cirrhosis. TMG will also decrease bilirubin, alkaline phosphatase, and several other liver enzymes related to a large variety of liver disorders. Significant liver benefits have been shown in 20 studies.
  • Longevity Formulations:As a part of a life extension formula. TMG has shown ability to protect interrogate of cellular DNA through methyl donation.
  • Methyl Donor Formulations: Along with B12, Folic acid, and Choline.
  • Due to its bi-polar nature, helps osmotic pressure in cells. For example it is used in salmon farming to protect fish against the problems of changing salt content. In humans, TMG maintains normal cellular electrolyte concentrations despite water and electrolyte losses during exercise. TMG also helps metabolize fats, which allows the body to burn fat rather than protein or muscle during exercise. The result is less cramping, increased endurance, and better utilization of fat stores

Here are some highlights from Nicolas  Rupcich’s  article on the potential exercise benefits of TMG consumption: 

The Power of Trimethylglycine (TMG) Supplementation

What benefits can be derived from supplementing with Trimethylglycine?

There have been several recent studies exploring the potential benefits of TMG supplementation, and most of them have yielded some impressive results. Nearly all studies examined a daily dosage of 2.5 grams of TMG. In many cases the dose was split with 1.25g twice per day.

While study designs varied between the clinicals, several benefits were perceived from supplementation with TMG at this level. Here’s a quick summary:

  • Weight-trained athletes taking 1.25g TMG twice daily increased muscle strength & power.
  • TMG supplementation increased markers of protein synthesis vs. placebo.
  • TMG enhanced endurance: allowing for more bench press reps, extended sprint capacity and more cycling power.
  • TMG has also demonstrated positive influence on anabolic environment – increased GH and IGF-1 levels, yet decreased cortisol.
  • Test subjects have increased muscle mass, arm size and decreased body fat.
  • Many studies were 10-15 days in nature, demonstrating the potential for rapid benefits.
  • One of the most recent studies in 2013 was 6 weeks long and showed that longer term TMG supplementation improved body composition, arm size, muscle power output and bench press work capacity.

So what’s net effect from all these results? Whether by means of improved cellular hydration, methyl donation or improved hormonal balance, trimethylglycine supplementation works. It improves muscle power output and endurance to enhance your workouts and maximize your time spent training. It is a vital supplement for those seeking optimal muscle power and performance.

Here is the article from Life-Enhancement Magazine:

Betaine Suppresses Inflammation During Aging: Possible Antiaging Effect

Betaine (also called trimethylglycine) is a nutritional component of many foods, including wheat, shellfish, spinach, and sugar beets.1 It is also available as an inexpensive dietary supplement. The function it serves in the plants that make it is to protect against osmotic stresses, such as drought, high salinity, or temperature stresses.

Earlier studies hypothesized that betaine contained in red wine and whole grain may play a role in the cardiovascular protective effect of those foods.1 It is also an important part of a major pathway for decreasing homocysteine in humans and other animals by contributing a methyl group for remethylating homocysteine to methionine.1

Betaine can be synthesized from choline, hence taking a betaine supplement is a way to spare choline for its other uses, such as to make acetylcholine and phosphatidylcholine.1 The authors of the paper (Ref 1) suggest that “… combined ingestion of folic acid and betaine may be the most effective method of lowering homocysteine.”

They also note that some of the studies in which betaine supplementation lowered homocysteine concentrations and improved some clinical conditions (including heart disease and glucose tolerance in both diabetic and nondiabetic subjects) lasted for 13–16 years, and betaine dosage was typically 6 grams per day.
A new study2 now reports that betaine suppresses certain pro-inflammatory signaling factors during aging, including NF-kappaB. NF-kappaB controls the transcription of a number of inflammatory molecules, including tumor necrosis factor (TNF), interleukins (ILs), chemokines, adhesion molecules, and inducible enzymes, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). All these inflammatory signaling agents are involved in conditions such as cancer, arthritis, and atherosclerosis.

[They are also involved in certain conditions where inflammation is on net beneficial, especially fighting infections. Therefore, one should be cautious in using powerful drugs that block these signaling pathways—unless one has a serious medical condition that requires that degree of inhibition—that’s why you need a knowledgeable doctor familiar with both prescription drugs and nutrition.

Otherwise, mild suppression of inflammation via appropriate dietary supplements would be the way to go for healthy people or those with only a non-severe degree of inflammatory pathophysiology (such as mild arthritis).]

This study is interesting because it looked at aging rats (Sprague-Dawley), which, like humans, have increasing levels of NF-kappaB in association with age, as well as with atherosclerosis, cancer, and other processes associated with oxidative stress and inflammation.2

“Recent reviews show that upregulated NF-kappaB activity seems to be a widespread biological phenomenon in aged animals and that NF-kappaB is a critical transcription factor involved in the pathogenesis of many disorders, including inflammatory diseases.”2
Betaine was added to regular rat chow at levels of 0.01%, 0.02%, or 0.04% and fed to 21-month-old rats for 10 days. On the basis that each rat ate on average 3 mg, 6 mg, or 12 mg of betaine, they ate 30, 60, or 120 mg/kg of body weight of betaine per day.

We suggest that, if you are not already taking betaine, you add it to your daily regimen. We both take it (Sandy takes 500 mg four times a day, and Durk takes 1 g four times a day).

References

  1. Betaine in human nutrition. Am J Clin Nutr80:539-49 (2004).
  2. Eun Kyung Go et al. Betaine suppresses proinflammatory signaling during aging: the involvement of nuclear factor kappa B via nuclear factor-inducing kinase/IkappaB kinase and mitogen-activated protein kinases. J Gerontol: Biol Sci60A(10):1252-64 (2005).

Here is Nicholas Rupcich’s full article:

The Power of Trimethylglycine (TMG) Supplementation

So what is Trimethylglycine?

Trimethylglycine or TMG is also more commonly referred to as betaine (BEET-ah-een). For the chemists, as the name implies it is a trimethyl derivative of the common amino acid glycine. TMG is commonly found in our diet in beets (that’s where the name betaine came from), whole grains, spinach and shellfish.

TMG can also be made in the body naturally via oxidation of choline-containing compounds. One of its primary functions in the body is to act as an ‘osmolyte’ and increase water retention of cells. It migrates in and out of cells to preserve cellular hydration state. Like creatine, a higher cellular trimethylglycine concentration can help preserve cell structure and make the cell more resilient to stress.

Another important function of TMG is that it also acts as a methyl group donor in creatine synthesis as well as conversion of homocysteine to methionine. Some studies have shown that TMG supplementation may lower plasma homocysteine levels, this is important since elevated homocysteine levels can lead to blood vessel inflammation, making it a risk for heart disease.

Beyond its potential heart health benefits, TMG has also been the subject of a range of studies for its performance benefits. These human trials demonstrate a significant improvement in physical performance, especially in muscle strength, power and endurance.

What benefits can I get from supplementing with Trimethylglycine?

There have been several recent studies exploring the potential benefits of TMG supplementation, and most of them have yielded some impressive results. Nearly all studies examined a daily dosage of 2.5 grams of TMG. In many cases the dose was split with 1.25g twice per day.

While study designs varied between the clinicals, several benefits were perceived from supplementation with TMG at this level. Here’s a quick summary:

  • Weight-trained athletes taking 1.25g TMG twice daily increased muscle strength & power.
  • TMG supplementation increased markers of protein synthesis vs. placebo.
  • TMG enhanced endurance: allowing for more bench press reps, extended sprint capacity and more cycling power.
  • TMG has also demonstrated positive influence on anabolic environment – increased GH and IGF-1 levels, yet decreased cortisol.
  • Test subjects have increased muscle mass, arm size and decreased body fat.
  • Many studies were 10-15 days in nature, demonstrating the potential for rapid benefits.
  • One of the most recent studies in 2013 was 6 weeks long and showed that longer term TMG supplementation improved body composition, arm size, muscle power output and bench press work capacity.

So what’s net effect from all these results? Whether by means of improved cellular hydration, methyl donation or improved hormonal balance, trimethylglycine supplementation works. It improves muscle power output and endurance to enhance your workouts and maximize your time spent training. It is a vital supplement for those seeking optimal muscle power and performance.

When is it optimal to take TMG? How much?

It’s quite evident from the consistency of the literature that the appropriate dosage of TMG is about 2.5 grams per day. Ideally it should be split in two doses 1.25g each; the first dose taken prior to training and the second either during or after your workout to replenish cellular stores.

There are no known serious side effects of trimethlyglycine supplementation, and the longer term 6 week study supports that. It is important to note that you should look closely at the source of the TMG in products you may be considering and ensure that is listed as ‘Trimethylglycine’ or ‘Betaine Anhydrous’ and NOT ‘Betaine Hydrochloride (HCl)’ which is commonly used as fish food or for low stomach acid related digestion issues.

Nicholas Rupcich 

Dr. Nicholas Rupcich holds a PhD in Biological Chemistry from McMaster University. He has over 10 years of experience in product development and formulation chemistry in the pharmaceutical and nutritional supplement industry, and has published numerous scientific paper and patents.

Here is another article excerpt from Jim Stoppani, PhD on this topic:

Jim Stoppani’s Expert Guide to Betaine

By Jim Stoppani, Ph.D. 

What are the Performance and Physique Applications? 

In the last few years, clinical studies have looked at betaine supplementation in a number of modalities, from strength, to muscle growth, to endurance and sprinting performance. What do they all have in common? Betaine left the placebo in the dust.

One of the first studies to look into betaine’s performance-supporting effects was done in my old lab at the University of Connecticut in 2010. The UCONN researchers found that weight-trained athletes taking 1.25 grams of betaine twice per day increased their muscle strength by 25 percent, and their muscle power by 20 percent.* They also determined that betaine significantly increased markers for muscle protein synthesis following a workout as compared to the placebo.*

Since this initial study, other researchers have found that betaine supplementation helped lifters complete more total reps in bench press workouts, pedal with more power in cycling workouts, and sprint for almost 40 seconds longer than subjects drinking just water. Like the similar-sounding beta-alanine, it has also been suggested to significantly lower levels of lactate, which can delay muscular fatigue and allow athletes to train harder, for longer.*

Researchers have found that betaine supplementation helped lifters complete more total reps in bench press workouts.

And then there’s the latest study on betaine, which comes from the College of Springfield in Massachusetts. Weight-trained males followed an undulating periodized weight-training program for six weeks.

One group supplemented with 1.25 grams of betaine twice per day and one group supplemented with a placebo twice per day. They reported that the subjects supplementing with betaine increased muscle mass by 4 pounds and arm size by 10 percent, all while decreasing body fat by 7 pounds.* The placebo group experienced no increase in muscle mass or arm size and no loss of body fat.

What’s to explain these incredible results? A recent study from UCONN indicated that these increases in muscle strength, power, and endurance may be due to betaine’s ability to increase levels of important anabolic substances while supporting a healthy balance of the catabolic hormone cortisol.*

Previous research also suggests that betaine supplementation increases nitric oxide and helps regulate cellular fluid volume, which could further promote muscle pump and overall muscle size.*

TMG is a compound which offers a spectrum of benefits ranging from mood modulation to cardiovascular health, exercise benefits and many more: it certainly warrants consideration as a core nutrient that most individuals could benefit from.

Biotics offers a Trimethylglycine Powder product, as well as a couple of other formulations which include TMG:

TMG Powder 

Categories:

Amino-Acids, AntiInflammatory, Antioxidants, Anxiety-Support, Brain-Support, Cellular-Metabolism, Detoxification-Liver, Immune-Support, Liver-Detox, Metals-Detoxification, NPN, Neurological-Support, New-Products, Powders, Seasonal-Promotions

Quantity: 8 oz. (240 g)

Description: TMG Powder (TRIMETHYLGLYCINE) Methyl Donor.

http://drlwilson.com/ARTICLES/TRIMTHYLGLYCINE.htm

Indications:

Use for Heavy Metal detoxification, especially Mercury and Copper, ADHD. neurological function and to reduce seizure activity. Helps to handle stress, improves oxygen utilization and enhances liver activity. Also used to enhance athletic performance. Also used to improve immune response, reduce tumours and to enhance anti-viral and anti-tumor defenses.

Benefits those with chronic fatigue, allergies, respiratory disorders, alcoholism and drug addiction. Also helps to reduce serum cholesterol and triglycerides and to normalize hypertension/glucose levels. It has been found beneficial to aid in sleep disorders. It is very important in the formation of collagen and is beneficial for connective tissue disorders of the ligaments, cartilage, arteries and veins. Helpful in reducing homocysteine levels.

Use if Hair Tissue result indicates a \”sympathetic dominance\” profile as this profile may be consistent with a \”fight or flight\” scenario. Also used for those with an MTHFR genetic or methylation defects.

Ingredients:

Trimethylglycine (Carboxmethyl) 3 grams per teaspoon

Suggestion:

Up to 1 teaspoon (3 grams) daily with food or as directed.

TMG is a compound which offers a spectrum of benefits ranging from mood modulation to cardiovascular health, exercise benefits and many more: it certainly warrants consideration as a core nutrient that most individuals could benefit from.

Bio-GGG-B

Categories: Adrenal-Support, AntiInflammatory, Cardiovascular-Support, Cellular-Metabolism, Digestion, Energy-Boost, Folic-Acid, Immune-Support, NPN, NeoNatal-Glandulars, Stamina, Vitamins

Quantity: 60 tablets

Description:

Phosphorylated B Vitamin Support. This product consists of 3 parts G fraction (riboflavin, niacin, folic acid, PABA and lipotrophic factors of choline, inositol & betaine and one part B fraction (thiamine, pantothenic acid and B12).

Indications: Use for inflammation, muscle spasms, and migraine headaches for increased riboflavin in hypertension, hyperlipidemia, night sweats, palm or sole of feet redness, edema, digestive difficulties, non-toxic goiter, inflammation, muscle spasms. Also indicated for those who “can’t get to sleep” at night”.

Ingredients:

Vitamin C 60 mg
Thiamin (B1) as cocarboxylase chloride) 2 mg
Riboflavin (B2) as riboflavin-5-phosphate) 6 mg
Niacin (as niacinamide) 20 mg
B6 (as P-5-P) 12 mg
Folate 800 mcg
Vitamin B12 (as methylcobalamin)
Biotin 300 mcg
Panothenic Acid (as calcium pantothenate) 10 mg
Inositol
Neonatal liver (bovine)
Choline (as bitartrate)
PABA (para-aminobenzoic acid)
Trimethylglycine

Suggestion: 2-4 tablets three times daily before meals or as directed.

Nutri-Clear NEW ADVANCED FORMULATION ACTIVATES AMPK

Categories: Alkalizing, Allergies, AntiInflammatory, Blood-Cleansing, Detoxification-Liver, Energy-Boost, Liver-Detox, Metals-Detoxification, NPN, Powders, Vegetarian

Quantity: 29.5 oz (836.3 grams) 1.84 lb

Description: Metabolic Clearing Formula Phase 1 and 2 Liver Detox: NEW ADVANCED FORMULATION!

Indications: Use for Metals detox.

ACTIVATES AMPK. AMPK is a master control mechanism for cellular energy homeostasis. It determines body fat composition and has a significant impact on mitochondrial biogenesis, the diabesity spectrum and life span extension in mice models. To support hepatic detoxification and GI tract healing; use for digestive inflammation, leaky gut syndrome, ulcers, rheumatoid arthritis, and food sensitivities; use with Livotrit Plus™ for hepatic clearing. Detoxification is a complex process that demands nutrients over and above what are needed for normal daily functioning.

Detoxification is an active process that involves at least two steps:
1) Oxidation: In a process that generates free radicals, an molecule of reactive oxygen is added to the toxin that is being processed. The purpose of this first step is to make the toxin ready for the second stage of the detoxification process. If nutrient supply is insufficient, then the first oxidative step may not proceed efficiently or the free radical damage from the biochemical reactions may increase oxidative stress and lead to tissue damage.

2) Conjugation: The second phase of detoxification is the conjugation stage, wherein a molecule such as taurine, glycine, or glutathione is covalently bound to the toxin to increase its solubility in water. After the conjugation step, the toxin is ready to be excreted in the bile or urine. If nutrients are not sufficiently available for this second step, then the oxidized toxin cannot be excreted efficiently and may cause secondary damage by interacting with body tissues and DNA

Ingredients:

Calories 120
Calories from Fat 20%
Total Fat 2g 3%
Saturated Fat 1.5g 8%
Cholesterol 0mg 0%
Sodium 300mg 13%
Potassium 460mg 13%
Total Carbohydrate 7g 2%
Dietary Fiber 1g 4%
Sugars 6g
Protein 17g 34%
Serving Size: 2 level scoops (approx. 33.5 g)
Not a significant source of iron.
Percent Daily Values based on a 2,000 calorie diet. Your Daily Values may be higher or lower depending on your calorie needs.

Daily Value Amount Per Serving

Ingredients: Pea protein isolate, organic evaporated cane juice, potassium citrate, calcium magnesium citrate, medium chain triglycerides, natural flavors, magnesium citrate malate, L-Glutamine, trimethylglycine, calcium ascorbate, stevia leaf extract, zinc picolinate, N-Acetyl-L-Cysteine, natural mixed carotenoids, d-alpha-tocopheryl acetate, quercetin, natural mixed tocopherols, manganese gluconate, molybdenum aspartate, pyridoxal-5-phosphate, L-Glutathione, L-Threonine, L-Lysine HCl, niacinamide, copper gluconate, calcium pantothenate, selenium aspartate, cocarboxylase chloride, riboflavin-5-phosphate, chromium picolinate, potassium iodide, vitamin D3, biotin, 5-methyltetrahydrofolic acid glucosamine salt, calcium folinate, and methylcobalamin.

*This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

ALSO CONTAINS (per serving):

**Trimethylglycine 500 mg
**L-Glutathione 10 mg
** N-Acetyl-L-Cysteine 50 mg
**L-Glutamine 500 mg
**Quercetin 25 mg

Suggestion: Blend, shake, or briskly stir 2 level scoops (44 grams) of NutriClear into 8 oz. of chilled water or the beverage of your choice.

References: Independent research and additional information
Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: clinical applications. JAMA. 2002 Jun 19; 287( 23): 3127-9

References

Homocysteine Levels Linked to Cognition Deficits: How Folate and Choline Help Keep You Sharp

  1. Craig SA. Betaine in human nutrition. Am J Clin Nutr. 2004 Sep;80(3):539-49.
  2. Atkinson W, et al. Dietary and supplementary betaine: acute effects on plasma betaine and homocysteine concentrations under standard and postmethionine load conditions in healthy male subjects. Am J Clin Nutr. 2008 Mar;87(3):577-85.
  3. Steenge, GR, et al. Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr. 2003 May;133(5):1291-5.
  4. Schwab, U., et al. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. Am J Clin Nutr. 2002 Nov;76(5):961-7.
  5. Graybiel A, et al. Use of betaine and glycocyamine… Ann West Med Surg 1951;5:863-75.
  6. Morrison LM. Results of betaine treatment of atherosclerosis. Am J Dig Dis 1952;19:381-4.
  7. Barak AJ, Tuma DJ. Betaine, metabolic by-product or vital methylating agent? Life Sci. 1983 Feb 14;32(7):771-4.
  8. Barak AJ, et al. Betaine effects on hepatic methionine metabolism elicited by short-term ethanol feeding. Alcohol. 1996 Sep-Oct;13(5):483-6.
  9. Barak AJ, et al. Dietary betaine promotes generation of hepatic S-adenosylmethionine and protects the liver from ethanol-induced fatty infiltration. Alcohol Clin Exp Res. 1993 Jun;17(3):552-5.
  10. Junnila M, et al. Reduction of carbon tetrachloride-induced hepatotoxic effects by oral administration of betaine in male Han-Wistar rats: a morphometric histological study. Vet Pathol. 2000 May;37(3):231-8.
  11. Junnila M, et al. Betaine reduces hepatic lipidosis induced by carbon tetrachloride in Sprague-Dawley rats. Vet Hum Toxicol. 1998 Oct;40(5):263-6.
  12. Wettstein M, et al. Betaine as an osmolyte in rat liver: metabolism and cell-to-cell interactions. Hepatology. 1998 Mar;27(3):787-93.
  13. Zapadniuk VI, et al. Corrective effect of trimethylglycine on the nicotinamide coenzyme and adenine nucleotide content of the tissues in experimental atherosclerosis. Farmakol Toksikol. 1986 Jul-Aug;49(4):71-3.
  14. Panteleimonova TN, Zapadniuk VI. Effect of trimethylglycine on lipid metabolism in experimental atherosclerosis in rabbit. Farmakol Toksikol. 1983 Jul-Aug;46(4):83-5.
  15. Zahn A, et al. Effects of methionine and betaine supplementation on growth performance, carcass composition and metabolism. Poult Sci 2006, 47:576-580.
  16. Maresh, CM, et al. The effects of betaine supplementation on strength and power performance. Medicine & Science in Sports & Exercise 39(5 suppl.): S304, 2007.
  17. Hoffman JR, et al. Effect of betaine supplementation on power performance and fatigue. J Int Soc Sports Nutr. 2009 Feb 27;6:7.
  18. Lee EC, et al. Ergogenic effects of betaine supplementation on strength and power performance. J Int Soc Sports Nutr. 2010 Jul 19;7:27.
  19. Trepanowski JF, et al. The effects of chronic betaine supplementation on exercise performance, skeletal muscle oxygen saturation and associated biochemical parameters in resistance trained men. J Strength Cond Res. 2011 Dec;25(12):3461-71.
  20. Pryor JL, Craig SA, Swensen T. Effect of betaine supplementation on cycling sprint performance. J Int Soc Sports Nutr. 2012 Apr 3;9(1):12
  21. Czapla, R., et al. Effect of betaine on cycling sprint power. J Int Soc Sports Nutr. 2010 Apr;7(Suppl 1):P23.
  22. Armstrong LE, et al. Influence of betaine consumption on strenuous running and sprinting in a hot environment. J Strength Cond Res. 2008 May;22(3):851-60.
  23. Apicella JM, et al. Betaine supplementation enhances anabolic endocrine and Akt signaling in response to acute bouts of exercise. Eur J Appl Physiol. 2013 Mar;113(3):793-802.
  24. Kraemer, W.J., et al. The influence of betaine supplementation on work performance and endocrine function in men. Annual Meeting of the National Strength and Condititoning Association, 2010.
  25. Cholewa, J. M., et al. Effects of betaine on body composition, performance, and homocysteine thiolactone. J Int Soc Sports Nutr. 2013 Aug;10:39
  26. Iqbal, O. Betaine induced release of tissue factor pathway inhibitor and nitric oxide: Implications in the management of cardiovascular disease. FASEB 2006 Mar; J 20: A655.
  27. Lever M, Slow S. The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem. 2010 Jun;43(9):732-44.
  28. Craig, S. S., et al. The betaine content of sweat from adolescent females. J Int Soc Sports Nutr. 2010 Jan;7:3Copyright © 2015 R. V. Lamberton & Associates,
    All rights reserved.

    Robert Lamberton ConsultingFunctional Medicine Consultant: Biotics ResearchProduct Formulator of Professional Nutraceutical Products

    Nutritional Therapy Practitioner (NTP) (c)

    Certified Light/Darkfield Microscopy Nutritionist

    Contributing Writer / Advisory Board Member:

    Nutricula: The Science of Longevity Journal   

    Healthy Organic Woman Magazine

    Twitter: rob_lamberton 

 

APRIL 7, 2016

ADRIAN RODRIGUEZ

Prior to 2012, all health products for pets were regulated by either the Veterinary Drugs Directorate (VDD, drugs) or the Canadian Food Inspection Agency (CFIA, feed and certain feed supplements). These agencies took more of a pharmaceutical approach, with complex, expensive and lengthy assessment timelines. Today, Canada has a simpler and more transparent registration system in place for registering pet supplements.

In 2012, Health Canada partnered with a third party Program Administrator, North American Compendiums (NAC), and created the Low-Risk Veterinary Health Products (LRVHP) Interim Notification Program (INP).

This notification programallows LRVHP to obtain market access for pet supplements in Canada by issuing Notification Numbers (NN, valid for one year and renewed annually) provided certain conditions and requirements are met. The program applies to products generally recognized as veterinary natural health products or supplements used orally or topically and intended for dogs, cats and horses that are not intended for food.

Products intended for other species, or routes of administration, are still required to undergo the normal pre-market approval regulatory process (i.e., achieve DIN registrations).

Products meeting the defined criteria are limited to products that contain active medicinal ingredients that are identified as low risk; and which have general health claims; which attest to GMP requirements for LRVHP; with evidence to support their safety and efficacy; and with the appropriate labeling including any applicable risk information statements.

The INP program maintains the list of substances considered to be low risk. Because the list is not within the regulations, it can be updated and ingredients are regularly added.  Our firm has been successful in adding ingredients to this list.

From its inception, the program was voluntary but this became a source of confusion for industry as some companies understood the voluntary nature of the program to mean that no registration or approval was needed for these product types. In truth, the voluntary nature of the program means that should a company not wish to undergo assessment of their product via the INP, the normal approval process would still need to be followed through either the VDD or the CFIA. In other words, not achieving an NN for a pet supplement would mean a company would have to achieve a DIN instead, which is considerably more costly and time-consuming. This new system provides a framework that is more proportional to the safe nature of these products.

It is also important to make the distinction that the INP program is not exactly a pre-market approval process. In other words, a Notification Number does not hold the same market authorization as say a DIN or NPN. But achieving an NN keeps enforcement/compliance away from your doorstep, which is important for anyone launching health products in Canada.

It is worth noting that the INP is a temporary program. Health Canada continues to work on a framework for veterinary NHPs similar to the system overseen by the Non-Prescription and Natural Health Products Directorate (NNHPD); however, we are not aware of when this new program will be available although we hope Health Canada will unveil its plans this year. It is commonly thought (and discussed) that achieving an NN under this temporary program will grandfather the product into the new licensing system coming in the years ahead.

 

 January 26, 2016
Functional Medicine Updates

Biotics Canada has just announced the availability of a much anticipated new product: Vegetable Source Lithium: Lintel-Zyme.

In this newsletter article, we detail some of the benefits of supplemental Lithium as well as health issues it may be useful for.

We also include an article on Lithium from Life Enhancement Magazine written by Will Block.

Here is some information on Lintel-Zyme:

For those of you who are looking for a great vegetable source Lithium, we now have Lintel-Zyme approved.

This is a vegan product and works to support the following: Adrenals, Brain and Cellular Metabolism, Depression, Thyroid and Emotional support as well as those under excessive Stress. This product is derived from vegetable source Lentils and is:

Specially grown, biologically active vegetable culture containing PHYTOCHEMICALLY BOUND LITHIUM and other phytochemicals including polyphenolic compounds with SOD and catalase, dehydrated at low temperature to preserve enzyme factors. Gluten and dairy free.
Regards,

Rob Lamberton

Robert Lamberton Consulting

Functional Medicine Consultant: Biotics Research

Product Formulator of Professional Nutraceutical Products

Nutritional Therapy Practitioner (NTP) (c)

Certified Light/Darkfield Microscopy Nutritionist

Contributing Writer / Advisory Board Member:

Nutricula: The Science of Longevity Journal 

Healthy Organic Woman Magazine

Twitter: rob_lamberton   Skype: larch60 

LinkedIn ID

Email: Rob@BioticsCan.com

Phone: 778-227-4952

Lithium, the mineral known for its efficacy against bipolar disorder, has become one of the most effective go-to  treatments for mental health.

Many authorities believe it to be a vital trace mineral and an essential nutrient and there exists a provisional recommended daily allowance (RDA) for adults at 1 mg per day. [1]

Benefits of Lithium

  • Neuroprotective
  • Increases neuronal survival
  • Increases Neurotrophic factors: BDNF, NGF, GDNF
  • Helps remodel the brain and heart (VEGF)
  • Promotes focus and attention
  • Induces autophagy
  • Increases neurogenesis (new neurons)
  • Increases stem cells in the hippocampus
  • Calming and stabilizes mood
  • Decreases insulin resistance
  • Reduces autoimmunity and inflammation
  • Increases bone density
  • Can help entrain our circadian rhythm
  • Longevity
  • Inhibits Plaques and Tangles (as in Alzheimer’s)
  • Protects brain cells from toxicity
  • Promotes brain cell regeneration
  • Increases gray matter of the brain
  • Regulates brain neurotransmitters
  • Supports healthy mood balance
  • Improves blood sugar metabolism
  • Potential therapeutic support for Tourette Syndrome
  • Helps Balance Obsessive-Compulsive Behaviors

Conditions that Lithium May Help

Autism
Aggression
Alzheimer’s Disease
Anxiety
ADHD/ ADD
Bipolar Disorder
Brain Injury due to vaccines; Methylmercury (thimerosal), toxins
Cerebral Palsy
Cluster Headaches
Depression and Mood Disorders
Childhood Epilepsy
Alcoholism and Drug Recovery
Liver disease; Hepatitis, Cirrhosis
Herpes Simplex Viruses (HSV 1 & 2)
Measles Virus
Adenovirus (Common Cold)
Epstein – Barr virus (Mononucleosis)
Neutropenia
Chronic Fatigue Syndrome
Migraine Headaches
Fibromyalgia
Glaucoma
Grave’s Disease (Hyperthyroidism)
Post Traumatic Stress Disorder (PTSD)
Stroke, Transient Ischemic Attack (TIA)

Can Lithium Benefit Brain Health? 

New research shows this element to have a variety of neuroprotective properties

By Will Block

Remember when people thought that mental illnesses, such as schizophrenia or chronic depression, were “all in the mind”? You do? Then you may be “youth-challenged,” because it’s been many years since that quaint old idea bit the dust. We’ve known for a long time that mental disorders are the result of physical and chemical disturbances in the brain—but deducing the molecular mechanisms involved is a tremendous challenge for neuroscientists. Some diseases are at least partially understood at that level, but many others remain mysterious.

The human brain is the most complex object in the known universe, so it’s perhaps forgivable that we haven’t figured it all out yet. Not to mention the ultimate paradox: the only thing we have with which to understand the workings of our brains is . . . our brains. (That one gives some philosophers nightmares.)

Meanwhile, neuroscientists keep trying to unravel the mysteries of the brain, bit by bit, while clinicians keep looking for newer and better ways to treat mental disorders—whether the neuroscientists can explain the rationales for them or not. Often the time lapse between discovering that something works and understanding why it works is very long indeed. One example is the use of lithium for treating bipolar disorder, also called manic-depressive illness or just manic depression. This is the disease in which, for no apparent reason, the patient’s mood and behavior alternate between the extremes of mania (a kind of exaggerated and unfounded elation) and depression, usually in cycles of months or years.

Lithium Works—But How?

We’ve known for half a century that lithium can control the mood extremes of bipolar disorder, and lithium-based drugs have been successfully used as therapy during that time. Lithium’s mechanism of action on the brain is still unknown, however. It has been speculated—and there is some evidence for this—that it may affect the levels of the neurotransmitters serotonin and norepinephrine in the brain. There is also evidence that lithium inhibits the action of inositol monophosphatase and several other enzymes that play key roles in mood-related neuromodulation (a complex type of signaling process related to neurotransmission).

And now there is growing evidence that lithium may provide some degree of protection against the brain damage that is characteristic of neurodegenerative diseases, such as Alzheimer’s. Before we discuss this exciting new avenue in dementia research, however, let’s talk a bit more about the use of lithium in treating bipolar disorder.

Lithium Is Still the Treatment of Choice

Long before anyone knew about lithium, let alone neurotransmitters or enzymes, it had been noticed that the waters of certain mineral springs seemed to have curative powers for people suffering from mania or depression. In the second century A.D., the Greek physician Seranus Ephesios recommended “natural waters such as alkaline springs” as a treatment for mania. Over the ensuing two millennia, countless people have “taken the waters” for a variety of ailments, real and imagined, at fashionable (and not so fashionable) spas throughout the world, particularly in Europe.

We now have an idea why these waters often seemed to helped manic individuals calm down, or depressed individuals perk up: it may have been not just the soothing spa ambience, but perhaps also the lithium in the water, which the spa clients were encouraged to drink as well as to soak in.

Lithium is so effective in controlling the mood extremes of bipolar disorder that to this day it is still the treatment of choice, even though a variety of effective, but sometimes dangerous, synthetic drugs have also come on the scene. The fact that lithium controls both mania and depression (the former more effectively than the latter) is both wonderful and puzzling, as it suggests that both of these conditions are, somehow, symptoms of the same underlying neurochemical disturbance.

It’s sobering to realize, though, that bipolar disorder goes beyond mere molecular imbalances: it also entails measurable losses of brain matter owing to neuronal death in a number of regions of the brain, including the hippocampus, a region that is also particularly hard hit by neuronal loss in Alzheimer’s disease.

Lithium Therapy Requires Careful Management

A typical maintenance dosage at which lithium (usually in the form of lithium carbonate) is prescribed for controlling bipolar disorder is 900 milligrams of the carbonate per day, which is equivalent to 170 mg of elemental lithium.* This is about 50 times greater than the amount of lithium (3.5 mg) contained in 1 liter of water from the famous Vichy mineral springs in France, and it’s hundreds of times greater than the trace amounts that we normally ingest with our food (about 200–600 micrograms per day). Thus, by either spa-water standards or nutritional standards, the therapeutic dosages of lithium are very high. That would be all right but for one thing: these therapeutic dosages are perilously close to being toxic dosages—not a good situation for any kind of medicine. For every patient, therefore, the physician must individualize and carefully monitor the treatment to avoid toxic overdose.

*The lithium is in the form of lithium ions, of course. The maintenance dosage produces plasma lithium-ion concentrations of about 0.6 mill moles per liter, which represents the low end of the desired “therapeutic range” of about 0.6–1.5 mill moles per liter (4–10 milligrams per liter). For laboratory studies with cell cultures, researchers generally use lithium solutions within this range of concentrations so as to mimic real-life clinical conditions, and for animal studies they use dosages that will produce plasma lithium-ion concentrations in this same range.

At these high levels, there are also many potential side effects of lithium, ranging from minor to severe. Among the most common (and benign) are dizziness, drowsiness, diarrhea, nausea, vomiting, excessive urination and thirst, a metallic taste, shakiness, tremors, and weight gain.

 

Lithium Inhibits Plaques and Tangles

Lithium solutions (usually lithium chloride or lithium carbonate) in the therapeutic range or beyond have been used in several recent laboratory and animal studies, and one human study, that have intriguing implications for preventing or inhibiting the progression of Alzheimer’s disease.
One such study dealt with the relationship between two of the three most characteristic neuroanatomical features of Alzheimer’s: the formation in the brain of harmful proteinaceous deposits called amyloid-beta plaques and neurofibrillary tangles.1 Both of these contribute to the death of brain neurons—which is the third characteristic feature. It turns out that the plaques are partly responsible for the formation of the tangles, and the researchers discovered that lithium (at about 10 times the therapeutic dosage) blocked this process in cultured rat cortical neurons, resulting in a strong protective action against neuronal death. In effect, the lithium protected against the neurotoxicity of amyloid-beta (which is also called beta-amyloid).

In a related study, researchers used mouse cortical neurons and live mice that were bred to be highly susceptible to Alzheimer’s disease.2 They found that treatment with lithium in therapeutic doses (for 3 weeks in the case of the live mice) sharply reduced the production of amyloid-beta in the first place, apparently by inhibiting the action of an enzyme, glycogen synthase kinase-3-alpha (GSK-3-alpha), that is required for this process to occur, as well as for the production of neurofibrillary tangles. The reductions observed were in the range of 40–78%. [Certain nonsteroidal anti-inflammatory drugs (NSAIDs) also reduce amyloid-beta levels, by the way, and the authors speculated that combination therapy with lithium and an NSAID might have an enhanced effect.*]

*It’s tempting to speculate that another agent, the Indian spice turmeric, may also be beneficial against the neuropathology of Alzheimer’s, as has been suggested in the scientific literature.3 Turmeric’s most active component is curcumin, an antioxidant, anti-inflammatory compound known to have a variety of important health benefits, including strong antitumor activity.
Lithium Protects Against Neuronal Death

In a third study, researchers examined the effects of lithium on glutamate-induced excitotoxicity, which is neuronal death caused by excessive amounts of glutamate, the brain’s most prevalent neurotransmitter.4 This phenomenon has been strongly implicated in the origin of a variety of neurodegenerative diseases, including dementia. The researchers found that lithium in the therapeutic range largely prevented glutamate-induced excitotoxicity in rodent cortical neurons. It apparently did so by stimulating the production of a protective protein called brain-derived neurotrophic factor, or BDNF, which is vital for the development and maintenance of healthy neurons (neurotrophic means pertaining to neural nutrition). Evidence for this mechanism came from the observation that when an antibody that neutralizes BDNF was added to the culture, lithium’s neuroprotective effect was blocked.

Lithium Stimulates New Neuronal Growth

Protecting neurons from destruction is one thing; it’s quite another to stimulate the growth of new neurons—a process called neurogenesis.* Numerous factors can affect neurogenesis, and lithium is apparently one of them. Researchers treated mice with lithium in dosages that produced plasma concentrations equivalent to those in the human therapeutic range; then they killed the mice and examined their brains.5 They found a 25% increase in the number of dividing cells in a structure of the hippocampus called the dentate gyrus—a clear indication of neurogenesis. This fit with the fact that lithium is known to stimulate production of a brain protein called B-cell lymphoma protein-2 (bcl-2) in certain areas of rodent brains; bcl-2 not only actively protects neurons from a variety of threats, including apoptosis (programmed cell suicide), but also promotes new cell growth. (Hippocampal neurogenesis has also been observed with a variety of antidepressants, so lithium’s action in this regard is not unique.)

*Until the late 1990s, it was widely believed that neurogenesis could not occur in adult human brains. We now know, however, that it can occur, and does.

 

A Lithium Primer

Lithium is an odd element that most people don’t know much about. Like the more familiar elements sodium and potassium, lithium is an alkali metal, and its chemical properties derive from that fact. It’s the lightest of all metals, with a density only half that of water. Thus it floats in water, with which it reacts chemically, producing hydrogen gas. It also reacts rapidly with oxygen, and it’s the only element that reacts with nitrogen at room temperature. With such extreme chemical reactivity, it obviously can’t be stored in air or water, so it’s usually stored in kerosene, with which it does not react. Lithium is so soft that it can be cut with a knife.

Not surprisingly, lithium (from the Greek lithos, meaning stone) is never found in nature as the free metal, but only in the form of stable chemical compounds (from which the free metal can be produced). These compounds are found in small amounts in nearly all igneous rocks (rocks formed by volcanic action), but the primary sources of lithium are the alkaline waters of many mineral springs and certain salt lakes, such as Searles Lake in California.

The main uses of lithium are in batteries, medicines, alloys (it increases corrosion resistance and tensile strength), lubricants, ceramic glazes, nuclear reactors, and hydrogen bombs.

Lithium compounds are found in trace amounts in fish, processed meat, dairy products, eggs, potatoes, and vegetables; we ingest only about 200–600 micrograms of lithium daily. Although lithium is not one of the nine trace elements that are vital for human nutrition (because without them, life itself would not be possible), it is one of the 14 (and perhaps more) auxiliary trace elements that are believed—with widely varying degrees of evidence—to be essential for our health

Lithium Increases Gray Matter

Finally, researchers at the Wayne State University School of Medicine in Detroit studied ten human patients (average age 33) with bipolar disorder.6 For 4 weeks they gave the patients a daily therapeutic dosage of lithium (they didn’t specify the actual dosage, but rather the plasma lithium-ion concentration that resulted from it—about 0.8 mill moles per liter, which would have required roughly 1000 mg per day of lithium carbonate). They then did magnetic resonance imaging (MRI) of the patients’ brain and compared the scans with those taken at the outset of the study. In eight of the ten patients’ brains, the lithium treatment significantly increased the total volume of gray matter: the average increase was 3%, corresponding to a volume of about 24 cm3 (1.5 in.3). The authors attributed the effect to lithium’s neurotrophic properties and its ability to stimulate the growth of such non-neuronal objects as glial cells, but they did not describe it as neurogenesis.

Lithium Might Be Helpful in Alzheimer’s

In all five of the studies outlined above, the researchers concluded their reports with statements to the effect that their results, along with those of various other recent studies, point to the possibility that long-term treatment with lithium might prove useful for reducing brain damage and stimulating new neural growth in neurodegenerative diseases such as Alzheimer’s.

That’s encouraging, and it illustrates the value of looking constantly for new (or old) and better ways to attack the problem of Alzheimer’s disease and other age-related diseases, so that we can all look forward to longer, healthier, happier lives.

References

  1. 1.     Alvarez G, Muñoz-Montaño JR, Satrústegui J, Avila J, Bogónez E, Díaz-Nido J. Lithium protects cultured neurons against beta-amyloid-induced neurodegeneration. FEBS Lett1999 Jun 25;453(3):260-4.
    Phiel CJ, Wilson CA, Lee VM-Y, Klein PS. GSK-3-alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 2003 May 22; 423(6938):435-9.
    3.     Calabrese V, Scapagnini G, Colombrita C, Ravagna A, Pennisi G, Giuffrida Stella AM, Galli F, Butterfield DA. Redox regulation of heat shock protein expression in aging and neurodegenerative disorders associated with oxidative stress: a nutritional approach. Amino Acids 2003 Dec;25(3-4): 437-44.
    4.     Hashimoto R, Takei N, Shimazu K, Christ L, Lu B, Chuang D-M. Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity.Neuropharmacology 2002 Dec;43(7):1173-9.
    5.     Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK. Enhancement of hippocampal neurogenesis by lithium. J Neurochem 2000 Oct; 75(4):1729-34.
    6.     Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK. Lithium-induced increase in human brain grey matter. Lancet 2000 Oct 7;356(9237): 1241-2. Erratum:Lancet 2000 Dec 16;356(9247):2104.

Special Note:

An excerpt from The Importance of Lithium Supplementation by Jonathan V. Wright, M.D.

Using Lithium Safely

Over a decade ago, a woman visited the Tahoma Clinic on the advice of her psychiatrist. She was severely bipolar, requiring a maximum dose of lithium carbonate to keep her symptoms under control. Despite close monitoring of serum lithium levels to maintain a safe range, she was starting to show many signs of lithium toxicity, including hypertension, tremor, nausea, and protein in her urine. She and her psychiatrist had tried other medications, but none provided the control of her bipolar symptoms that lithium did. So she came to the Tahoma Clinic to see if there were any natural options for her.

Fortunately, there was a simple solution. Without changing her lithium dose, the clinic doctor treating her asked the woman to start taking 1 tablespoon of flaxseed oil along with 800 IU of vitamin E (mixed tocopherols) three times a day. One month later, the woman’s blood pressure had normalized, her tremors and nausea were gone, and there was no further protein in the urine. And best of all, her bipolar symptoms remained under control. At that point, she was able to cut the flaxseed oil to 1 tablespoon daily along with 400 IU of vitamin E. Several years later, herlithium toxicity hasn’t returned.

To be on the safe side, we always recommend that anyone taking lithium also take a teaspoonful or two of fish oils (or other essential fatty acid such as BIOMEGA-3) along with 400 IU of vitamin E (as mixed tocopherols) each day.
This example involved the prescription drug lithium carbonate, not lithium orotate and yet the toxic symptoms were still reversed and then prevented from returning with a simple few supplements that people should be taking every day anyway.
Edited by Susan Hartman, Co-Founder and Content Editor of The Triad of Life, Inc.

Related Articles: 
·         Lithium Orotate: Misleading Research
·         Lithium – The Misunderstood Mineral Part 1
·         Lithium – The Misunderstood Mineral Part 2
·         Potential Role for Lithium in Preventing Alzheimer’s Disease
·         The Safe, Unique Mineral with Multiple Uses

Sources used in the preparation of this article include:

Top 13 Health Benefits of Lithium (orotate, aspartate, carbonate, chloride)
by Joseph M. Cohen

7 Benefits of Lithium
by Dr. Edward Group DC, NP, DACBN, DCBCN, DABFM

Can Lithium Benefit Brain Health? 

By Will Block

Lithium – Online Holistic Health

References:

Schrauzer GN. Lithium: occurrence, dietary intakes, nutritional essentiality. The Journal of the American College of Nutrition. 2002 February;21(1):14-21.

  1. Monkul ES, Matsuo K, Nicoletti MA, Dierschke N, Hatch JP, Dalwani M, Brambilla P, Caetano S, Sassi RB, Mallinger AG, Soares JC. Prefrontal gray matter increases in healthy individuals after lithium treatment: a voxel-based morphometry study.Neuroscience Letters. 2007 December 11;429(1):7-11.
  2. Chuang DM. Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodenerative diseases? Critical Reviews in Neurobiology. 2004;16(1-2):83-90.
  3. Zamani A, Omrani GR, Nasab MM. Lithium’s effect on bone mineral density. Bone. 2009 February;44(2):331-4. doi: 10.1016/j.bone.2008.10.001.
  4. Bolton JM, Metge C, Lix L, Prior H, Sareen J, Leslie WD. Fracture risk from psychotropic medications: a population-based analysis. Journal of Clinical Psychopharmacology. 2008 August;28(4):384-91. doi: 10.1097/JCP.0b013e31817d5943.
  5. Vestergaard P. Skeletal effects of central nervous system active drugs: anxiolytics, sedatives, antidepressants, lithium and neuroleptics. Current Drug Safety. 2008 September;3(3):185-9.
  6. Clément-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssiere B, Belleville C, Estrera K, Warman ML, Baron R, Rawadi G. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice.Proceedings of the National Academy of Sciences U.S.A. 2005 November 29;102(48):17406-11.
  7. Maria Flavia Dorrego, Ph.D.; Lilia Canevara, M.D.; Gabriela Kuzis, Ph.D.; Liliana Sabe, Ph.D.; Sergio E. Starkstein, M.D., Ph.D. A Randomized, Double-Blind, Crossover Study of Methylphenidate and Lithium in Adults With Attention-Deficit/Hyperactivity Disorder: Preliminary Findings. The Journal of Neuropsychiatry and Clinical Neurosciences 2002;14:289-295.
  8. Erickson HM Jr, Goggin JE, Messiha FS. Comparison of lithium and haloperidol therapy in Gilles de la Tourette syndrome. Advances in Experimental Medicine and Biology. 1977;90:197-205.
  9. J Lieb. The anti-prostaglandin, immunostimulating and antimicrobial properties of lithium and antidepressants. Ecancermedicalscience. 2008; 2: 88.
  10. Szuster-Ciesielska A, Tustanowska-Stachura A, Slotwinska M, Marmurowska-Michalowska H, Kandefer-Szerszen M.        In vitro immunoregulatory effects of antidepressants in healthy volunteers. Polish Journal of Pharmacology. 2003 May-Jun;55(3):353-62.
  11. Lieb J. Lithium and antidepressants: inhibiting eicosanoids, stimulating immunity, and defeating microorganisms. Medical Hypotheses. 2002 October;59(4):429-32.
  12. Zarse K, Terao T, Tian J, Iwata N, Ishii N, Ristow M. Low-dose lithium uptake promotes longevity in humans and metazoans. European Journal of Nutrition. 2011 August;50(5):387-9. doi: 10.1007/s00394-011-0171-x.
  13. de Vasconcellos AP, Nieto FB, Crema LM, Diehl LA, de Almeida LM, Prediger ME, da Rocha ER, Dalmaz C. Chronic lithium treatment has antioxidant properties but does not prevent oxidative damage induced by chronic variate stress. Neurochemical Research. 2006 September;31(9):1141-51.
  14. Rasmussen SA. Lithium and tryptophan aumentation in clomipramine-resistant obsessive-compulsive disorder. The American Journal of Psychiatry. 1984 October;141(10):1283-5.
  15. Pallanti S, Haznedar MM, Hollander E, Licalzi EM, Bernadi S, Newmark R, Buchsbaum MS. Basal Ganglia activity in pathological gambling: a fluorodeoxyglucose-positron emission tomography study. Neuropsychobiology. 2010;62(2):132-8. doi: 10.1159/000317286.

Copyright © 2016 R. V. Lamberton & Associates, All rights reserved.

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January 14, 2016
Functional Medicine Updates

Most readers of this publication will have some familiarity with PS (Phosphatidylserine) and its benefits, especially for cognitive function and brain health.

Like many natural source compounds, PS has been shown through published research to provide a plethora of health benefits which we would not immediately think of.

In this article, we will review the commonly understood benefits of PS, and highlight some of the lesser known health benefits of this remarkable compound.

PS: A Review

First, let’s do a quick review of PS, and it’s well known benefits:

Phosphatidylserine (PS) is a phospholipid that is found in all cells, but is most highly concentrated in the walls (membranes) of brain cells, making up about 70% of its nerve tissue mass. There it aids in the storage, release and activity of many vital neurotransmitters and their receptors. Phosphatidylserine also aids in cell-to-cell communication.

Phosphatidylserine is involved in the upkeep and restoration of nerve cell membranes. Among its list of functions, phosphatidylserine stimulates the release of dopamine (a mood regulator that also control physical sensations, and movement), increases the production of acetylcholine (necessary for learning and memory), enhances brain glucose metabolism (the fuel used for brain activity), reduces cortisol levels (a stress hormone), and boosts the activity of nerve growth factor (NGF), which oversees the health of cholinergic neurons.

Research has shown that dietary supplementation with phosphatidylserine can slow and even reverse the decline of learning, mood, memory, concentration, word recall related to dementia or age-related cognitive impairment in middle-aged and elderly subjects.[1]

Phosphatidylserine can help prime the brain back to a more youthful level of activity in a number of ways.

Key Health Benefits of PS Include:

  • Fight Cognitive Decline and Protect Your Brain
  • There’s a strong relationship between declining PS levels and declining cognitive performance.
  • Researchers have found that phosphatidyl helps reduce symptoms of diseases, such as Alzheimer and Parkinson’s
  • The FDA has even authorized the use of labels stating, “consumption of phosphatidylserine may reduce the risk of dementia and cognitive dysfunction in the elderly”
  • One study found that the daily use for 12 weeks was able to significantly reduce symptoms of Alzheimer’s disease
  • In a randomized double-blind, placebo-controlled study, hospitalized patients with dementia given the compound showed significant reductions in symptoms after 3 weeks
  • Researchers think this may due to its positive effect on acetylcholine levels, which is a necessary neurotransmitter for cognitive function
  • Another study involving rats found that after 8 days, the compound reversed age-dependent decreases in acetylcholine
  • This compound strengthens the inner cell membrane and directly enhances communication between brain cells
  • In one double-blind, placebo-controlled study, PS supplementation was associated with improvements in memory and learning processes as well as time taken to complete tasks
  • PS has even been shown to reduce symptoms of ADHD in children and depression
  • Another study where healthy, young adults given a dose of phosphatidylserine for 2 weeks experienced a whopping 20% improvement in processing speed, accuracy by responding with 13% more correct answers, and 39% less wrong answers compared to a placebo
  • EEG studies have further confirmed that PS supplementation is associated with more relaxed states after stressful activities
  • PS plays an important role in maintaining the hormonal balance in the body
  • PS can also help provide protection from free radicals damage
  • Depression – Preliminary research indicates that phosphatidylserine holds promise in the treatment of depression. In a 2004 study published in Progress in Neuropsychopharmacology and Biological Psychiatry, for example, tests on rats demonstrated that phosphatidylserine may offer an antidepressive effect
  • Stress
  • In addition, phosphatidylserine supplements are purported to preserve memory, promote healthy sleep, and improve mood
  • Phosphatidylserine is also very important for the cell apoptosis
  • It also enhances the performance of the immune system.
  • PS is found to be of great importance because it increases the number of membrane receptor sites for receiving the chemical messages.
  • Scientific studies reveal that phosphatidylserine is essential for releasing neurotransmitters
  • ADHD
  • Using phosphatidylserine in combination with omega-3 fatty acids may aid in the treatment of ADHD in children, suggests a 2012 study published in European Psychiatry.

For the study, 200 children with ADHD were assigned to 15 weeks of treatment with either a placebo or supplements containing phosphatidylserine and omega-3 fatty acids. Study results revealed that participants treated with the combination of phosphatidylserine and omega-3 fatty acids experienced a significantly greater reduction in hyperactive/impulsive behavior and a greater improvement in mood (compared to those given the placebo)
“PS might be an important tool aimed at conserving memory, learning, concentration, and other higher mental capacities in the face of advancing age.”

– Parris M. Kidd, PhD, Alternative Medicine Review
Food Sources

Phosphatidylserine is available in a number foods, including soy, carrots, rice, egg yolks, chicken liver, and beef liver

What particularly caught our attention was a study published in 2008 indicating dramatic improvements following exercise – specifically cortisol level reduction, testosterone level increases and an improvement in cortisol: testosterone ratios:

J Int Soc Sports Nutr. 2008; 5: 11.
Published online 2008 Jul 28. doi:  10.1186/1550-2783-5-11
PMCID: PMC2503954The effects of phosphatidylserine on endocrine response to moderate intensity exerciseMichael A Starks,1 Stacy L Starks,1 Michael Kingsley,2 Martin Purpura,3 and Ralf Jäger3
Abstract
BackgroundPrevious research has indicated that phosphatidylserine (PS) supplementation has the potential to attenuate the serum cortisol response to acute exercise stress. Equivocal findings suggest that this effect might be dose dependent. This study aimed to examine the influence of short-term supplementation with a moderate dose of PS (600 mg per day) on plasma concentrations of cortisol, lactate, growth hormone and testosterone before, during, and following moderate intensity exercise in healthy males.ResultsMean peak cortisol concentrations and area under the curve (AUC) were lower following PS (39 ± 1% and 35 ± 0%, respectively) when compared to placebo (p < 0.05). PS increased AUC for testosterone to cortisol ratio (184 ± 5%) when compared to placebo (p < 0.05). PS and placebo supplementation had no effect on lactate or growth hormone levels.ConclusionThe findings suggest that PS is an effective supplement for combating exercise-induced stress and preventing the physiological deterioration that can accompany too much exercise. PS supplementation promotes a desired hormonal status for athletes by blunting increases in cortisol levels.

More testosterone, less cortisol after training with phosphatidylserine

Phosphatidylserine improves the body’s hormonal response to training. Men given a daily dose of 600 mg for ten days in a row produced more testosterone and less cortisol than men who didn’t take phosphatidylserine after fifteen minutes of exercise.

This was the conclusion that researchers at the University of Mississippi drew after performing an experiment with ten healthy men. The subjects had to cycle for fifteen minutes a couple of times, and also did five ‘sets’ of three minutes. Each ‘set’ started with a moderate level of effort – about 65 percent of the VO2max – and ended with 85 percent intensity.

The researchers measured the concentrations of cortisol, testosterone, lactate and growth hormone in the subjects’ blood before and after the exercise. During one of the sessions the men took phosphatidylserine and during the other session a placebo.

Phosphatidylserine is found in the membranes of cells. When taken as a supplement it improves the receptors’ function and resistance to stress. Exactly how it works is not known, but small-scale human studies have shown that phosphatidylserine lowers cortisol concentrations after exercise and exposure to stress. That was the reasoning behind the research we’re talking about here. The researchers wanted to know whether they could improve hormonal response using a fairly simple supplement. After all, less cortisol and more testosterone means more progression.

Sports scientists often use the ratio between cortisol and testosterone as an indicator of how easily the body builds up muscle. That’s why some sports scientists advise athletes to do power training early in the evening: testosterone levels may well be somewhat lower than earlier in the day, but cortisol levels are radically lower at this time of the day.

The researchers found no effect on the concentration of lactate in the blood, and statistically speaking phosphatidylserine had no significant effect on the growth hormone levels. But looking at the curve you’d be forgiven for thinking differently. Oh well, you can’t have everything.

Phosphatidylserine is found in lecithin, but you’d have to take an awful lot of lecithin to reach the dose used by the researchers. One hundred grams of lecithin contains about fifteen milligrams of phospholipids, and only a small amount of these is made up of phosphatidylserine.

Source: J Int Soc Sports Nutr. 2008; 5: 11.

Links to the articles which were sourced in the preparation of this article include the following:

Phosphatidylserine

Uses for Phosphatidylserine

How Phosphatidylserine benefits your body

Phosphatidylserine: A “Must Have” Bodybuilding Supplement

Phosphatidylserine (PS) The Essential Brain Nutrient

Biotics offers a Phosphatidylserine product:

Phosphatidylserine

Categories: Adrenal-Support, Brain-Support, Neurological-Support

Description: Mood Disorders

Indications:

For cognitive conditions such as concentration, short-term memory loss, mood disorders, as well as for senility, myelin sheath repair, enhanced brain glucose metabolism, increased release of dopamine, adrenal cortical hyperfunction (increased cortisol levels), and to increase cell membrane integrity

With dramatically increasing rates of dementia and Alzheimer’s Disease in the general population, Phosphatidylserine represents a natural compound which can help to prevent the development of these devastating conditions, however it also provides an extensive array of health benefits and certainly should be considered for these applications.

Regards,

Rob Lamberton

Copyright © 2015 R. V. Lamberton & Associates, All rights reserved

Robert Lamberton Consulting

November 7, 2015Functional Medicine Updates

 

This fascinating article posted on Prevent Disease.com refers to a study may provide a new tool for dealing with those in the patient population that deal with glucose metabolism issues.

This study (in mice) indicates that supplementation with L-Arginine may dramatically improve glucose metabolism in both insulin sensitive  and insulin resistant metabolisms by upwards to 40 %.

L-Arginine is a relatively inexpensive amino acid and its utilization may prove to be a valuable addition to blood sugar / diabetic protocols as well as being relatively inexpensive from the patient’s perspective.

Now by no means of course would we suggest that simple supplementation with L-Arginine is an effective and comprehensive solution to resolving blood sugar / Diabesity Spectrum issues in a patient: as you well know, when a patient presents with this kind of issue, many other factors and issues need to be taken into account.

Other issues that need to be addressed include:

  • Hormonal balance
  • Sleep
  • Inflammation
  • Diet
  • Stomach acidity / potential Hypochlorhydria
  • Hydration
  • Exercise
  • Heavy metals
  • POP’s (persistent organic pollutants)
  • Infectious agents
  • Excretory pathway functionality (liver, gall bladder, kidneys, GI tract etc.)
  • Gut health
  • Circulatory system
  • Mitochondrial function
  • And others

Berberine of course is an effective herbal compound which in published studies has proven to be equally efficacious to Metformin, one of the standard pharmaceuticals used for blood sugar/Diabetes issues, however Berberine provides a number of benefits that Metformin does not which make it stand out.

Here is a link to a great article on this topic from the Life Enhancement website:

Of significance with regards to this differentiation between Berberine and Metformin are cardiovascular benefits provided by Berberine and not by Metformin as well as neuroprotective benefits (and increasingly of course the significance of insulin levels, mitochondrial function, inflammation and insulin resistance in the brain are being documented as key factors in neurodegenerative conditions to the extent that now Alzheimer’s is now being referred to as Type lll Diabetes in some published research)

And also of significance is the fact that Berberine activates AMPK (5′ AMP-activated protein kinase) which in our opinion is still not given enough consideration when addressing health issues with patients,  given its widespread and significant impact on many metabolic pathways and functions.

We previously did a couple of snewsletter articles on AMPK, which you can review here:

AMPK – Mitochondrial Biogenesis Visceral Fat Loss Anti-Aging Inflammation – and More.pdf

AMPK Review Article.pdf

Here is the article on Arginine and glucose  metabolism:

Supplementation with the amino acid arginine, commonly found in almonds and hazelnuts, could help to improve glucose metabolism by as much as 40%, according to new research in mice. The study shows that supplementation with the amino acid significantly improves glucose metabolism in both insulin-sensitive and insulin-resistant metabolisms.

More than 371 million people worldwide suffer from diabetes, of whom 90% are affected by lifestyle-related diabetes mellitus type 2 (type 2 diabetes). In new experiments, researchers from the University of Copenhagen working in collaboration with a research group at the University of Cincinnati, USA, have demonstrated that the amino acid arginine, found in salmon, eggs, and nuts, improves glucose metabolism significantly in both lean (insulin-sensitive) and obese (insulin-resistant) mice.

“In fact, the amino acid is just as effective as several well-established drugs for type 2 diabetics,” says postdoc Christoffer Clemmensen.                                                                                                           He has conducted the new experiments based at Faculty of Health and Medical Sciences, University of Copenhagen.

He is currently conducting research at the Institute for Diabetes and Obesity at Helmholtz Zentrum Munchen, the German Research Centre for Environmental Health in Munich.

Even better than nuts are less energy-dense foods such as salmon and eggs, said Clemmensen.

Clemmensen said he expects similar results in human trials. “However, a key issue for future studies is to explore what doses of arginine can be tolerated by humans and to confirm that there are no adverse effects associated with arginine supplementation. It may be that the best strategy is to create a ‘dietary cocktail,’ including several nutrients all known to [aid] glucose metabolism.”

What researchers have found is that L-arginine potentiation of glucose-induced insulin secretion occurs independently of NO.

Italian researchers–specialists in diabetes, endocrinology, and metabolic diseases–knew that long-term arginine supplementation improves insulin sensitivity and endothelial function in type 2 diabetic patients who are not obese, because that had already been demonstrated.

Their own earlier study in 2001 showed that chronic administration of arginine improved insulin sensitivity in lean type 2 diabetic patients, but not in obese ones. Previously, German researchers had shown that arginine improved endothelial function to a similar extent as physical exercise did, and arginine together with exercise produced an additive effect.

“We have demonstrated that both lean and fat laboratory mice benefit considerably from arginine supplements. In fact, we improved glucose metabolism by as much as 40% in both groups. We can also see that arginine increases the body’s production of glucagon-like peptide-1 (GLP-1), an intestinal hormone which plays an important role in regulating appetite and glucose metabolism, and which is therefore used in numerous drugs for treating type 2 diabetes,” says Christoffer
Clemmensen, and continues:

“You cannot, of course, cure diabetes by eating unlimited quantities of arginine-rich almonds and hazelnuts. However, our findings indicate that diet-based interventions with arginine-containing foods can have a positive effect on how the body processes the food we eat.”

The research findings were recently published in the American scientific journal Endocrinology under the heading Oral l-arginine Stimulates GLP-1 Secretion to Improve Glucose Tolerance in Male Mice.

Study Details

To test the effect of the amino acid arginine, researchers subjected lean and obese animal models to a so-called glucose tolerance test.
They found that arginine improves glucose metabolism significantly in both lean (insulin-sensitive) and obese (insulin-resistant) mice.

“We can also see that arginine increases the body’s production of glucagon-like peptide-1 (GLP-1), an intestinal hormone which plays an important role in regulating appetite and glucose metabolism, and which is therefore used in numerous drugs for treating type 2 diabetes,” said Clemmensen.

“Mice without GLP-1 receptors are not affected to the same extent by arginine,” he added. “There is no perceptible improvement in glucose metabolism or insulin secretion, confirming our hypothesis of a close biological connection between GLP-1 and arginine.”

“This exciting result has raised several new questions which we want to investigate. Can other amino acids do what arginine does?

Supplementation With Arginine

Supplemental dosages of 6 to 8 grams L-Arginine per day are considered safe. Although available in food, for some applications such as stimulating secretion of growth hormone from the pituitary, it is not released quickly enough as the food is digested. The supplemental doses taken on an empty stomach will arrive at the blood-brain barrier without competition. Then growth hormone secretion will be stimulated which in turn can affect glucose metabolism.

Sources:

news.ku.dk
life-choice.net
nih.gov
endojournals.org

Dave Mihalovic is a Naturopathic Doctor specializing in vaccine research, cancer prevention and a natural approach to treatment.

Robert Lamberton Consulting

Functional Medicine Consultant: Biotics Research                                                                                                                                                                                                                                         Email: Rob@BioticsCan.com
Phone:
778-227-4952

 

Functional Medicine Updates

Quercetin is a well known nutritional compound which is readily available as a nutritional supplement both as a stand alone item and also as an ingredient in multi-ingredient nutritional supplement formulations.

And it has many health benefits, a summary of which appears in the following article.

In this edition of our newsletter, we detail some newly published research which discusses how consumption of quercetin by its action of getting rid of senescent cells has the potential to enhance health over time (in this article referred to as “Healthspan”) – as well as potentially extending lifespan.

And we introduce to you in this article some terminology which may be new to you:

Senolytics – which are compounds that selectively induce the death of senescent cells

This article originally appeared in Life Enhancement Magazine: here is the article

By getting rid of senescent cells …

Quercetin Prolongs Healthspan and May Extend Lifespan

Senescence Accelerates Aging

In a recent “tour de force” scientific study, researchers at The Scripps Research Institute (TSRI), the Mayo Clinic, and other institutions began with the assumption that the accumulations of senescent cells have been associated with accelerated aging.1Senescent cells have stopped dividing and secrete compounds that both harm surrounding tissue structure and raise the odds of nearby cells also becoming senescent. Scripps et al searched for ways to eliminate senescent cells in the body that have become destructive, hypothesizing that the outcome would be beneficial for overall health.

Their study, published online a few months ago in Aging Cell, documents the discovery of increased expression of pro-survival networks in senescent cells. The researchers found that senescent cells were similar to cancer cells in that they possessed an increased expression of so called pro-survival networks that help them resist apoptosis, aka programmed cell death.

Senescent cells were similar to cancer cells in that they possessed an increased expression of so called pro-survival networks that help them resist programmed cell death.
Inducing Senescent Cell Self-Destruction

The scientists conjectured that the pro-survival, protective mechanisms of senescent cells could be altered in ways to cause self-destruction. Based on their hypotheses, they identified two compounds, a nutrient and a drug—chosen from screening 46 agents—that could induce apoptosis (cell suicide) of senescent cells in vitro and in vivo, leading to improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan in mice developed to age rapidly. These mice age at six times the rate of normal mice, and in the study their healthy lifespans, or “healthspans” were greatly extended by 10 percent. They also had more than 15 percent greater bone density. Astonishingly, dramatic improvements were noticeable just days after treatment.

Senolytics can help delay, prevent, improve, or even reverse several chronic age-related diseases and disabilities as a group, rather than concentrating on one at a time.
Senolytics: Anti-Aging Intervention in Humans?

Dubbed senolytics, these compounds consist of the nutrient quercetin and the drug dasatinib. Separately and together, the new research shows that they selectively kill senescent cells. What is amazing is that senolytics directly target the source of the majority of free radicals. This is the same source that Denham Harman observed 65 years ago.2

The researchers documented how senolytics can help delay, prevent, improve, or even reverse several chronic age-related diseases and disabilities as a group, rather than concentrating on one at a time.

If senolytics work in humans, it could truly be an “anti-aging” intervention.
Quercetin: Many Benefits and Few Side Effects

The nutrient quercetin—widely found as a flavonol in fruits and vegetables—is a nutritional supplement that acts as an antihistamine,3 anti-inflammatory,4 and anti-cancer agent5 among many other benefits, including:

  • Quercetin’s natural metabolites of dietary quercetin target and protect macrophages from becoming foam cells6
  • Quercetin extends lifespan in C. elegans7
  • Quercetin decreases high-fat diet induced body weight gain8
  • Quercetin is more effective as an anti-diabetic than as an anti-obesity biomolecule9
  • Quercetin increases insulin sensitivity and improves glucose tolerance10
  • Quercetin exhibits cardioprotective properties through an anti-atherogenic gene11

 

Throughout our lifetimes, stem cells renew our muscles and blood vessels. 
They also do the same for skin and blood cells that turn over rapidly.

Dasatinib’s Adverse Effects

Dasatinib is a cancer drug, sold under the trade name Sprycel.® It is not at home in the human body and has many adverse effects. For example, it may increase the risk of a rare but serious condition in which there is abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension, PAH). Symptoms of PAH may include shortness of breath, fatigue, and swelling of the body (such as the ankles and legs). In reported cases, patients developed PAH after starting dasatinib, including after more than one year of treatment. Aside from that, the cost of dasatinib is also outrageously high; a daily dose is $367 per day!
On the other hand, quercetin has been used as a supplement for a long time, is very low-cost, and has very few side effects compared to dasatinib.

In the study, quercetin showed a greater effect against both senescent humanendothelial cells and senescent mouse bone marrow mesenchymal stem cells, while dasatinib was found to reduce senescent human fat cell progenitors.
Mesenchymal stem cells are multipotent stromal cells (connective tissue cells of any organ) that can differentiate into a variety of cell types. These include bone cells, cartilage cells, muscle cells, and fat cells (see Fig. 1). Throughout our lifetimes, stem cells renew our muscles and blood vessels. They also do the same for skin and blood cells that turn over rapidly.

Also, the combination of quercetin and dasatinib eliminate senescent mouse embryonic fibroblasts. Senolytics are now thought to combat some of the factors associated with aging as other research indicates (see Fig. 2). Scientists project that other anti-senescent senolytics are on the way.

Fat cells are arguably one of the most abundant types of senescent cells in humans.
What Is the Human Equivalent Dose of Quercetin?

The dose of quercetin used in the study was 50-mg per kg body weight in mice given weekly. Using the FDA’s “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers” (see http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf), that would be about 283 mg for a 70 kg (154 lb) person.

This is considered to be a safe dose, and many supplement formulations already use this amount or more on a daily basis. The amount of dasatinib given weekly to the mice was 5-mg kg body weight or 28 mg for a 154 lb person. These are small amounts indeed. However, there are so many adverse effects reported that its use at any level might be a problem.

The Discovery of Senescent Cells

The human fibroblast cell line that Leonard Hayflick used in the discovery of the famous Hayflick limit, demonstrated that cells would replicate only a limited number of times before becoming terminally senescent.
Senescent cells don’t immediately die but they no longer replicate and they undergo many negative changes not found in non-senescent cells.
Senescent cells are not generally beneficial to have around, other than the fact that their exit from the cell cycle acts as a protective mechanism against those cells becoming cancerous.

 

The Hayflick limit was one of the  earliest findings in which the processes that impair the function of aging cells started to be discovered.

In fact, a growing population of senescent cells with age has been found to have a damaging effect on the functioning of non-senescent cells in their cellular neighborhood. This is because they sustain, for example, chronic inflammation and extracellular matrix remodeling. The Hayflick limit was one of the earliest findings in which the processes that impair the function of aging cells started to be discovered.

The Underlying Concept

The Senescent Transcriptome and Anti-Apoptotic Pathways

In the study, the scientific collaborators initially tested their hypotheses by comparing gene expression insenescent vs. nonsenescent cells using transcript array analysis.They focused on fat cell progenitors, or preadipocytes (fat cells), as they are arguably one of the most abundant types of senescent cells in humans.12 From the perspective of this study, this could lead one to conclude that our fat cells are killing us!

Cultures were split and senescence induced in half of the cells. Twenty-five days later, gene expression was measured using gene chips. Overall patterns of gene expression differed substantially between senescent and nonsenescent preadipocytes isolated from the same subjects. Analyses of gene categories indeed revealed upregulation of negative regulators of apoptosis and antiapoptotic gene sets in senescent compared to nonsenescent cells.

While not mentioned in the Scripps et al study, the chromosomes in stem cells continually lose their telomeres and when they become too short to divide they are said to become “senescent.” Importantly, when these cells senesce they stop dividing, losing their functions, and becoming moribund. At this point, they eventually poison nearby tissue, thus creating more senescent cells.

Figure 1 Mesenchymal stem cells effects on various tissues of the body.

 

 

In the mice that had their senescent cells removed by employing the trigger, a 20 to 25% increase in lifespan followed and this was from a single treatment, quite late in life.

Defunct stem cells poison the body with chemical inflammatory signals (cytokines) that spread the “fire” of what has been called inflam-aging. These age-associated changes involve the overexpression of inflammation and immune response genes and also genes associated with the lysosomal system (which breaks down cell garbage, as in autophagy).
Even though senescent cell abundance in aging or diseased tissues is low—achieving a maximum of 15 percent of nucleated cells in very old primates13—senescent cells can secrete pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which together constitute the senescence-associated secretory phenotype (SASP).
Just a small number of senescent cells can cause a great deal of damage. That’s like saying that even if only 15% of the “apples” in your basket are “bad apples,” that is enough to kill you.

Removing Senescent Cells Increased Lifespan

Mice whose bodies were cleared of senescent cells didn’t live longer—but they did live better, which means that destroying senescent cells might also prolong our golden years, thus enhancing our healthspans. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 2;479(7372):232-6.

In the earlier research conducted by many of the same scientists who worked on the Scripps Research Institute study (see Fig. 1), the question was asked about whether senescent cell removal could affect lifespan.14 Using genetically modified mice in such a way that senescent cells would self-detonate if a trigger was pulled, by feeding the mice a molecule that matched the trigger, the researchers could cause the senescent cells to terminate themselves while leaving normal cells intact. Comparing the same mice, not triggered and triggered into self-immolation, the results were amazing.

In the mice that had their senescent cells removed by employing the trigger, a 20 to 25% increase in lifespan followed and this was from a single treatment, quite late in life.

Unlike the earlier study, the research group at Scripps et al started with gene expression profiles for senescent cells, comparing them to profiles for non-senescent cells. They determined that the target for the drug and nutrient agents that keeps senescent cells alive—when they really should be eliminating themselves—should be identified through RNA interference to silence these genes, one at a time.

This they thought would help identify effective strategies for differentially targeting the senescent cells. As already mentioned, they screened 46 compounds to see which would best attack the targets they had identified.
Summarizing their findings: the nutrient quercetin seemed to work best for endothelial cells (in arteries), and dasatinib was best for fat stem cells. Quercetin is cheap and found in many herbs and berries; dasatinib is a patented chemotherapy agent, sold for a scandalously high price by Bristol Myers Squib, the maker of dasatinib.
Senescent cells are cells that have stopped dividing, which accumulate with age and accelerate the aging process.
The Results Could Be Transformative

“We view this study as a big, first step toward developing treatments that can be given safely to patients to extend healthspan or to treat age-related diseases and disorders,” said TSRI Professor Paul Robbins, PhD, who with Associate Professor Laura Niedernhofer, MD, PhD, led the research efforts for the paper at TSRI in Florida. “When senolytic agents, like the combination we identified, are used clinically, the results could be transformative.”15

“The prototypes of these senolytic agents have more than proven their ability to alleviate multiple characteristics associated with aging,” said Mayo Clinic Professor James Kirkland, MD, PhD, senior author of the new study. “It may eventually become feasible to delay, prevent, alleviate or even reverse multiple chronic diseases and disabilities as a group, instead of just one at a time.”15

Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells. A combination of the two was most effective overall.
Identifying the Target

To repeat, senescent cells are cells that have stopped dividing, which accumulate with age and accelerate the aging process. Since the “healthspan” (defined as the time in life free of disease) in mice is enhanced by killing off these cells, the scientists reasoned that if they could accomplish this in humans, the results could open the doors to tremendous treatment potential.

How should they go about identifying and targeting senescent cells without damaging other cells? Their suspicion was that senescent cells’ resistance to death by stress and damage could provide a clue. By using transcript analysis, as described above, the researchers found that this common characteristic of cancer and senescent cells provided the clue.

When they increased the expression of “pro-survival networks” both cancer and senescent cells were better able to resist apoptosis (programmed cell death) and this finding provided key criteria to search for potential drug candidates.
Using these criteria, the team honed in on two available compounds—the cancer drug dasatinib and quercetin, a natural supplement, as we already know.

Further cell culture testing showed that these compounds do indeed selectively induce death of senescent cells. As already outlined, each of the two agents had different strong points. To repeat, dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells. A combination of the two was most effective overall.

“In animal models, the compounds improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan,” said Niedernhofer, whose animal models of accelerated aging were used extensively in the study. “Remarkably, in some cases, these drugs did so with only a single course of treatment.”15

“Senescence is involved in a number of diseases and pathologies so there could be any number of applications for these and similar compounds,” Robbins said. “Also, we anticipate that treatment with senolytic drugs to clear damaged cells would be infrequent, reducing the chance of side effects.”15 However, if it turned out that most of the “drugs” were nutrients, without significant adverse effects, infrequent treatment would not be an issue.

Old mice given a single dose of both senolytics exhibited improved cardiovascular function within five days.
Remarkable Results

Old mice given a single dose of both senolytics exhibited improved cardiovascular function within five days. After seven months mice weakened by radiation therapy used for cancer treatment showing improved exercise capacity. Healthspan was also extended in mice models with accelerated aging that were periodically administered the drugs, with age-related symptoms of spine degeneration and osteoporosis delayed.

Barking up the Wrong Tree

In the study’s conflict of interest section, runs the following: “Mayo Clinic, JK, TT, YZ, TP, NG, AP [initials of the authors] have a financial interest related to this research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. LJN and PDR are co-founders of, and have an equity interest in, Aldabra Bioscience.”

As passionate health seekers, we need to make every effort to avoid this at all reasonable costs and that includes the use of our minds to stay on top of the relevant fields of rapidly growing knowledge.
The Point Is Not Only Living Longer…

The point is living healthier. If you look only at longevity, you may overlook the horror of outliving yourself. This means outliving your ability to have a healthy, meaningful, productive life. That makes healthspan a necessary and adjunctive aspect of research in the area.

While it is more and more likely that we will live into our eighties and nineties, for far too many of us, it may be more like a jail sentence, in which our life at those ages consists of debilitation and all that that entails. Slowly decaying away, physically and mentally, in assisted living facilities and nursing centers where we are treated like cattle. As passionate health seekers, we need to make every effort to avoid this at all reasonable costs and that includes the use of our minds to stay on top of the relevant fields of rapidly growing knowledge.

Biotics formulations which include quercetin include the following:

BioProtect Plus

Broad-spectrum vitamin (A, C, E), mineral (zinc, selenium, potassium), enzyme (CoQ10, SOD, catalase), amino acid (glutathione, methionine, taurine, NAC), antioxidant formulation to prevent free radical damage from pollution, chemicals, and smoke, psychological and physical stress, electromagnetic radiation, and muscle soreness due to exercise-induced lactic acid

Nutri-Clear

Indications: Use for metals detox.

To support hepatic detoxification and GI tract healing; use for digestive inflammation, leaky gut syndrome, ulcers, rheumatoid arthritis, and food sensitivities; use with Livotrit Plus™ for hepatic clearing. Detoxification is a complex process that demands nutrients over and above what are needed for normal daily functioning.

Detoxification is an active process that involves at least two steps:

1) Oxidation: In a process that generates free radicals, an molecule of reactive oxygen is added to the toxin that is being processed. The purpose of this first step is to make the toxin ready for the second stage of the detoxification process. If nutrient supply is insufficient, then the first oxidative step may not proceed efficiently or the free radical damage from the biochemical reactions may increase oxidative stress and lead to tissue damage.

2) Conjugation: The second phase of detoxification is the conjugation stage, wherein a molecule such as taurine, glycine, or glutathione is covalently bound to the toxin to increase its solubility in water. After the conjugation step, the toxin is ready to be excreted in the bile or urine. If nutrients are not sufficiently available for this second step, then the oxidized toxin cannot be excreted efficiently and may cause secondary damage by interacting with body tissues and DNA

Pro-Multi Plus

Use as a Multi Vitamin/Mineral Product where higher nutrient levels are required

ResveraSirt-HP

A specialized formulation to support vascular integrity and healthy aging

VasculoSirt

AntiInflammatory, Antioxidants, Cardiovascular-Support, Cholesterol-Reduction, Folates, Glucose-Balancing

Regards,

Rob Lamberton
Copyright © 2015 R. V. Lamberton & Associates, All rights reserved

References

1.    Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-58. doi: 10.1111/acel.12344. Epub 2015 Apr 22.
2.    Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;2:298–300.
3.    Sakai-Kashiwabara M, Abe S, Asano K. Suppressive activity of quercetin on the production of eosinophil chemoattractants from eosinophils in vitro. In Vivo. 2014 Jul-Aug;28(4):515-22. PubMed PMID: 24982217.
4.    Boots AW, Drent M, de Boer VC, Bast A, Haenen GR. Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis. Clin Nutr. 2011 Aug;30(4):506-12. doi: 10.1016/j.clnu.2011.01.010. Epub 2011 Feb 15. PubMed PMID:21324570.
5.    Brito AF, Ribeiro M, Abrantes AM, Pires AS, Teixo RJ, Tralhão JG, Botelho MF. Quercetin in cancer treatment, alone or in combination with conventional therapeutics? Curr Med Chem. 2015 Aug 12. [Epub ahead of print] PubMed PMID:26264923.
6.    Kawai Y, Nishikawa T, Shiba Y, et al. Macrophage as a target of quercetin glucuronidesin human atherosclerotic arteries: implication in the anti-atherosclerotic mechanism of dietary flavonoids. J Biol Chem. 2008 Apr 4;283(14):9424-34. doi:10.1074/jbc.M706571200. Epub 2008 Jan 16. PubMed PMID: 18199750.
7.    Pietsch K1, Saul N, Chakrabarti S, et al. Hormetins, antioxidants and prooxidants: defining quercetin-, caffeic acid- and rosmarinic acid-mediated life extension in C. elegans. Biogerontology. 2011 Aug;12(4):329–47.
8.    Hoek-van den Hil EF, van Schothorst EM, van der Stelt I, et al. Quercetin decreases high-fat diet induced body weight gain and accumulation of hepatic and circulating lipids in mice. Genes Nutr. 2014 Sep;9(5):418. doi: 10.1007/s12263-014-0418-2. Epub 2014 Jul 22.
9.    Arias N1, Macarulla MT, Aguirre L, et al. Quercetin can reduce insulin resistance without decreasing adipose tissue and skeletal muscle fat accumulation. Genes Nutr. 2014 Jan;9(1):361. doi: 10.1007/s12263-013-0361-7. Epub 2013 Dec 14.
10.     Henagan TM, Cefalu WT, Ribnicky DM, et al. In vivo effects of dietary quercetin and quercetin-rich red onion extract on skeletal muscle mitochondria, metabolism, and insulin sensitivity. Genes Nutr. 2015 Jan;10(1):451–63.
11.      Lakshman R, Garige M, Gong M, et al. Is alcohol beneficial or harmful for cardioprotection? Genes Nutr. 2010 Jun;5(2):111-20. doi: 10.1007/s12263-009-0161-2.
12.     Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL. Fat tissue, aging, and cellular senescence.Aging Cell. 2010 Oct;9(5):667-84. doi: 10.1111/j.1474-9726.2010.00608.x. Epub 2010 Aug 15. Review. PubMed PMID: 20701600; PubMed Central PMCID: PMC2941545.
13.  Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev. 2007 Jan;128(1):36-44. Epub 2006 Nov 20. PubMed PMID: 17116315; PubMed Central PMCID: PMC3654105.
14.      Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 2;479(7372):232-6.
15.     Scripps Research Institute. [Internet] Scripps Research, Mayo Clinic Scientists Find New Class of Drugs that Dramatically Increases Healthy Lifespan. March 9, 2015. Available from
16.  https://www.scripps.edu/news/press/2015/20150309agingcell.html

Accessed August 18, 2015.
Robert Lamberton Consulting

Functional Medicine Consultant: Biotics Research

Contributing Writer / Advisory Board Member:

Nutricula: The Science of Longevity Journal 

 

 

CANNABIS OIL ALLOWED IN CANADA                                                                                                                                                                                                                                                                                     Yesterday, Health Canada released a statement on the Smith case, the result being they are now allowing licensed producers under the MMPR to manufacture cannabis oil for sale to Canadians. This is the first time a so-called “derivative” has been permitted for sale in Canada.

The changes are effective immediately, however licensed producers who have a licence to cultivate have to achieve a “supplemental licence” to start producing and selling cannabis oil to registered clients (see Section 56 Class Exemption for LP’s).

There are restrictions being imposed, notably the THC concentration must be no greater than 3% w/v (30 mg THC per 1mL oil). However, there does not seem to be a restriction on the concentration of other biomarkers such as CBD. There are also many extra requirements for labelling and packaging, but they’re unimportant details at this point. Pharmaceutical in nature.

What is particularly exciting is the allowance of capsules such as gelatin capsules containing cannabis oil. Similar to fish oil capsules. Now, the cannabis oil capsules cannot contain any flavour or scent, but there doesn’t seem to be a restriction on excipients at this time. For example, if the oil is quite thick, a diluent could be used to make filling easier. However, we have yet to understand excipient use.

All of this means that supercritical extraction techniques (and machinery) can now be legally imported into Canada and used by licensed producers to manufacture cannabis oil. Why this is exciting for the industry, is it is a positive step forward allowing the free sale of medical marijuana in dosage forms that are better suited to the health of Canadians. We wouldn’t give our children cigarettes; we wouldn’t give them a joint to smoke. Gel caps are a healthier solution that help with dosage compliance.

There are other changes, such as allowing individuals to make their own oils, so long as they don’t use organic solvents.

At the same time, Health Canada also released a variety of statements and bulletins covering a range of topics. For example, to date it has been suggested that a producer in Canada could import finished product grown in another country, rather than grow domestically; however, a recent bulletin suggests Health Canada would not allow this. It will take some time to digest everything they have published, please stay tuned.

Brian Wagner's picture

Article by Brian Wagner

Clinical Pearls for Health Care Professionals

 In this edition of our newsletter, we discuss the Nrf2 signalling pathway which is a master regulator of the total antioxidant system available in all human cells, and its significance in optimizing health as well as its compromised function playing a key role in the development of chronic, degenerative disease processes associated with the aging process.

We list some of the key areas of current research in which Nrf2 activation has been identified as having a potentially significant impact on these degenerative conditions as well as identifying pharmaceutical and natural compounds which can activate the Nrf2 pathway.

From a clinical application perspective, it is important to identify the state of activation of the Nrf2 pathway in your patients to be able to help them to optimize their quality of life, but also to be able to develop clinical protocols to be able to ameliorate chronic, degenerative conditions (you will already be familiar with many of the compounds which help to activate the Nrf2 pathway: this will provide you with some more comprehensive understanding on a metabolic regulation level why these compounds are so effective).

What is Nrf2?

From an article in Nature’s Pathway, Nrf2 is defined this way:
Nrf2 is short for NF-E2-related 2. It is a powerful protein that is present in each cell in the body but must be released by an Nrf2 activator. Once released, it moves to the nucleus of the cell and bonds to the DNA at the location that is the master regulator of the total antioxidant system available in all human cells.

The activated Nrf2 upregulate survival genes — genes that enable the cells to survive the stress from free radicals and other oxidants or inflammatory stress — and downregulate other genes to help the body function at an optimal level.

According to Dr. David Perlmutter, renowned Neurologist,

“High levels of free radicals turn on a specific protein in the cell’s nucleus called Nrf2.  Activation of Nrf2 essentially opens the door for the production of a vast array of our body’s most important antioxidants. It is clear that excessive free radicals induce better antioxidant production through this pathway, Nrf2 (NF-E2-Related Factor 2), a transcription factor in humans that is encoded by the NFE2L2 gene, regulates the expression of a set of antioxidant and detoxifying genes, protecting the body from the ravages of oxidative stress-related conditions, including (but not limited to) those affecting the brain and nervous system”.

“Nrf2 upregulates survival genes, regulates the expression of a set of antioxidant and detoxifying genes, protecting the body from the ravages of oxidative stress-related conditions, including (but not limited to) those affecting the brain and nervous system”.

Nrf2 research has been generating headlines such as these:

“The widespread nature of Nrf2 may have an important therapeutic potential, allowing prevention of carcinogenesis and neurodegenerative diseases.”

One of the major sources we used in the development of this newsletter content is a blog website:

Anti-Aging Firewalls (a great website to review)

Specifically, the author, Vince Guiliano wrote three separate articles on the Nrf2 signalling pathway:

The pivotal role of Nrf2. Part 1 – a new view on the control of oxidative damage and generation of hormetic effects

The pivotal role of Nrf2. Part 2 – foods, phyto-substances and other substances that turn on Nrf2

The pivotal role of Nrf2. Part 3 – Part 3 – Is promotion of Nrf2 expression a viable strategy for human human healthspan and lifespan extension?

Here are a couple of diagrams illustrating mechanisms associated with Nrf2:

The following is a list of some of the significant activities associated with Nrf2:

  • Nrf2 provides a response to stress
  • NRF2 is protective against multiple types of disorders associated with oxidative insults, for example airways disorders
  • Another important form of stress responded to by Nrf2 expression is nitrosative stress
  • Nuclear levels of Nrf2 and its expression generally decline with age
  • Some important positive biological effects of AMPK “The Master Metabolic Sensor and Regulator” such as its anti-apoptotic capabilities  are modulated by Nrf2
  • Nrf2 appears to stimulate the same pathways that extend life via calorie restriction or alternative day fasting
  • There appears to be significant cross-talk between the insulin signaling, NF-kappaB, and Nrf2 pathways
  • Associated with its interactions with insulin, treatment of diabetes may be based on targeting Nrf2
  • P62 protein appears to play an important role in oxidative defense through facilitating release of Nrf2 from Keap1. (P62 is involved in autophagy)
  • Decline in levels of p62 and disturbances in signaling of Nrf2 and other pathways can possibly contribute to the pathology of Alzheimer’s disease
  • Interventions affecting Nrf2 may also play key roles in control if inflammatory diseases
  • Nrf2 plays an important role in detoxification of drugs and other xenobiotics via upregulating expression of Phase 2 drug metabolizing enzymes
  • Nrf2 is protective against the oxidative stress induced by drinking alcohol and mediated by CYP2E1
  • Nrf2 and Parkinson’s disease
  • There seems to be a substantial interest in developing therapeutics for Parkinson’s disease that work via activating Nrf2 expression
  • Certain cancers work to epigenetically silence the expression of Nrf2.  Such may be the case, for example, in prostate cancers
  • Nrf2 activators may be of benefit to patients with chronic renal failure
  • Protection against the negative effects of strokes is another of the many medical benefits that might be possible through endogenous stimulation of Nrf2
  • Steady laminar blood flow (s-flow) results in activation of Nrf2 and consequent inhibition of oxidative stress and inflammation in the vessel wall and is atheroprotective.  By contrast, disturbed blood flow (d-flow) results in the activation of activator protein 1 (AP-1) and nuclear factor kappaB (NF-κB), inflammation, and predisposes to the development of plaques
  • Overexpression of Nrf2 is not always necessarioly a good thing.  It can result in protection of cancer cells
  • NRF2 is protective against forms of hearing loss

Activation of the Nrf2 pathway can impact on this development of inflammatory conditions via regulation by the “Antioxidant Response Element” (ARE)

– Electrophile Detoxification
– Glutathione Homeostasis
– Direct Antioxidants
– Proteasome System
– NER Pathway
– Anti – inflammatory Genes
– Antibacterial Peptides / Proteins

This pathway regulates the production of important molecules that impart antioxidant activity, such as glutathione and SOD (superoxide dismutase).  It also regulates the production of dextoxification enzymes, including glutathione S-transferase, and downregulates signaling factors such as NF-kB for a healthy response to inflammation.

It’s No Surprise: Nrf2 Research is Exploding:

“Recently the Michael J. Fox Foundation has launched an investigation into Nrf2 activation as a potential to slow or reverse the affects Parkinson’s disease.”

“Research for multiple sclerosis with BG-12, a Nrf2 activating bioengineered pharmaceutical looks most promising: recently, phase III clinical trials found that DMF (BG-12) successfully reduced relapse rate and time to progression of disability in multiple sclerosis.”

From an article in the Nutricology Newsletter, here is a list of key areas of current research:

  • Multiple Sclerosis
  • Parkinson’s Disease
  • Diabetes
  • Epilepsy
  • Huntington’s Disease
  • Cardiovascular Disease
  • Longevity

There are many natural Nrf2 activators

  • Exercise will activate the Nrf2 pathway
  • Intermittent fasting will also cause activation of Nrf2 and survival genes
  • Many foods cause Nrf2 activation, such as blueberries, tea, coffee, broccoli, cabbage, wasabi, Brussels sprouts and onions
  • A number of spices and herbs activate Nrf2, including milk thistle, bacopa, ashwaganda, green tea, turmeric, black pepper and pine bark

Foods and supplements can simultaneously affect multiple biological pathways related to health and longevity such as Keap1-Nrf2, N.

F-kappaB, GH-IGF, the heat shock response pathway (HSR), AMPK, FOXO and the unfolded protein response pathway (UPR). Further, these pathways can interact so as to reinforce or inhibit each other.

The way dietary flavonoids work to confer their multiple health effects, is probably mainly via the keap1-Nrf2 pathway.  That is substances which are both themselves antioxidants and activators of the keap1-Nrf2 pathway produce their main results through keap1-Nrf2 and activating the body’s own antioxidant and defensive systems.

From the Linus Pauling Institute Micronutrient Information center:

“Flavonoids are a large family of polyphenolic compounds synthesized by plants”.

Table 1: Common Dietary Flavonoids
(Select the highlighted text to see chemical structures.)Flavonoid SubclassDietary FlavonoidsSome Common Food SourcesAnthocyanidinsCyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, PetunidinRed, blue, and purple berries; red and purple grapes; red wineFlavanolsMonomers (Catechins):
Catechin, Epicatechin, Epigallocatechin Epicatechin gallate, Epigallocatechin gallate
Dimers and Polymers:
Theaflavins, Thearubigins, ProanthocyanidinsCatechins: Teas (particularly green and white), chocolate, grapes, berries, apples
Theaflavins, Thearubigins: Teas (particularly black and oolong)
Proanthocyanidins: Chocolate, apples, berries, red grapes, red wineFlavanonesHesperetin, Naringenin, EriodictyolCitrus fruits and juices, e.g., oranges, grapefruits, lemonsFlavonolsQuercetin, Kaempferol, Myricetin, IsorhamnetinWidely distributed: yellow onions, scallions, kale, broccoli, apples, berries, teas
Flavones
Apigenin, Luteolin
Parsley, thyme, celery, hot peppers,IsoflavonesDaidzein, Genistein, GlyciteinSoybeans, soy foods, legumes

Drugs that promote the expression of Nrf2

  • Metformin appears to extend lifespan and healthspan through activating AMPK and its influence on Nrf2, at least in nematodes
  • Lansoprazole – a Proton Pump Inhibitor – and possibly other PPI’s
  • Statins too appear to activate Nrf2
  • Histone deacetylase inhibitors can reverse toxicity-induced loss of Nrf2 expression: specifically, valproic acid and lithium can reverse depression in Nrf2 activity in astrocytes induced by the toxin lipopolysaccharide (LPS)

Nrf2 activity is an important mechanism of hormesis.

Dozens of dietary substances exercise hormetic effects via Nrf2.

(The general concept of hormesis is that a controlled amount of exposure to a body stressor may produce an overall positive effect. Hormesis involves, challenging cells and body systems by mild stress resulting in them becoming stronger and resistant to aging(ref))
A protective hormetic response to body injury or insult may involve simultaneous activation of HSP70 and Nrf2.

A large number of foods and supplements promote the expression of Nrf2

  • anthocyanins
  • carotenoids
  • terpenes
  • Compounds that possess an orthodihydroxy or quinone structure can interact with cellular proteins in the Keap1/Nrf2/ARE pathway to activate the transcription of antioxidant enzymes
  • Carotenoids
  • flavonoids
  • Curcumin
  • Ginger
  • Sulforphane
  • Red Ginsing can mitigate toxicity induced by polychlorinated biphenyls via Nrf2 and induction of HO
  • Coffee
  • Resveratrol
  • Green tea
  • A number of other less-familiar phytosubstances also work through Nrf2 to promote production of HO-1 and are health-protective
  • Dan Shen (a TCM medicinal herb which is very effective for CVD and other applications)
  • Lycopene and Fish oils
  • Olive oil
  • Ashitaba
  • Broccoli Sprout Extract  (Sulforaphane 0.04%)
  • Curcumin (95% curcuminoids)
  • Resveratrol / Stilbenes
  • Green Tea extract (50 % EGCG)
  • IP6 (Inositol Hexaphosphate plus Inositol)
  • Andrographis paniculata
  • Piperine
  • Shilajit (Adaptogen)
  • Pterostilbene (methylated Resveratrol)
  • Pomegranate
  • Ginkgo biloba
  • Oleuropein
  • Ashwagandha (Adaptogen)
  • Berry powder mixes
  • flavonoids such as quercetin from citrus fruits
  • genistein from soybean.
  • Sulfur-containing compounds can be generally classified into two major categories, namely, isothiocyanates including sulforaphane (SFN) from broccoli, phenethyl isothiocyanate (PEITC) from turnips and watercress, as well as allyl isothiocyanate from Brussels sprouts, and organosulfur compounds including diallyl sulfides from garlic oil
  • Ashitaba (chalcones)
  • Xanthumols
  • Chlorophyllin
  • Capsicum
  • Hydroxytyrosol
  • ALA
  • Gingko
  • Alpha tocopherol
  • Lycopene
  • Apple Polyphenols
  • Allyl Sulpides
  • Silymarin
  • Green tea

Many researchers see the Nrf2 pathway as being intrinsically involved with aging and longevity:
The naked mole rat is a good example: it lives eight times as long as comparable-size mice and has six times the amount of endogenous expression of Nrf2.
One view of aging is that it is associated with and partially driven by vascular oxidative stress which is directly linked with Nrf2 expression.
Contrarian research suggests that overexpression of Nrf2 could lead to aortic atherosclerosis, creating more harm than good.
Other contrarian research suggests that quality of antioxidant defense and longevity within a species may not be correlated.
AMPK expression appears to control the aging process.

AMPK signaling has positive impacts on both lifespan and healthspan, and this appears to apply across  a wide variety of species.
Multiple phytosubstances are promoters of AMPK and simultaneously are inhibitors of NF-kappaB and are activators of the Nrf2 pathway.
Health benefits associated with those substances are conferred by activation of antioxidant and hormetic response genes by Nrf2, by limitation of inflammation due to inhibition of NF-kappaB expression and by a variety of associated mechanisms.

Another key point:

The redox control pathways in which Nrf2 plays a key role and the NF-kappaB pathways controlling inflammation and driving many disease processes are in close interaction.

Is promotion of Nrf2 expression a viable strategy for human healthspan and lifespan extension?

The answer is probably YES based on the published research, some of which is summarized in this article.

Existing research does suggest that:

  1. Increasing Nrf2 expression can help prevent, ameliorate or clear up numerous age-related health problems in a variety of species, problems ranging from Type 2 diabetes to ischemic stroke, to cancers to cardiovascular problems to recovery from physical injuries.  To the extent diseases or conditions of infirmity can be prevented or cured people will live longer.  “Longevity is the art of not dying.”
  2. Nrf2 expression is clearly associated with control of aging in a number of species.  It is particularly high in certain long-lived species.
  3. Nrf2 expression can be practically increased by consuming a number of food substances, drugs and, particularly phyto-substance supplements such as the ones discussed in this article
  4. Increasing expression of Nrf2 cannot be considered independently from acting on tightly linked pathways such as inhibition of expression of NF-kappaB and its inflammatory concomitants.

Cardiovascular Disease: Alternative Hypotheses and Treatment Protocols 
(the Myogenic  and Unified Theories, Calcified Endosomal Death)
In this edition of our Biotics Newsletter we will focus on Cardiovascular Disease: we will share with you two alternative hypotheses on the etiology of Cardiovascular Disease and one published paper on a new hypothesis on the etiology of atherosclerosis (massively calcified endosomal death).

Also we have an update for you on our upcoming Genomics Training events as well as some intriguing links to papers on Saccaromyces boulardii benefits for Congestive Heart Failure, plus the importance of optimizing autophagy for minimizing inflammation (and its potential impact on CVD) – and more.

By reviewing this information, our objective is to enable you to potentially  gain new insights into  this prevalent health issue such that you can provide even better patient care for your patients, and provide you with some additional information for patient education.

By the numbers:

In Canada, the incidence of CVD is as follows:

(from the Heart and Stroke Foundation)

Cardiovascular disease deaths

Every 7 minutes in Canada, someone dies from heart disease or stroke (Statistics Canada, 2011c).

Heart disease and stroke are two of the three leading causes of death in Canada. These statistics are based on 2008 data (the latest year available from Statistics Canada).

In 2008 cardiovascular disease accounted for (Statistics Canada, 2011c):

  • 29% of all deaths in Canada (69,703 deaths – or more than 69,500)
  • 28% of all male deaths
  • 29.7% of all female deaths

In 2008, of all cardiovascular deaths (Statistics Canada, 2011c):

  • 54% were due to ischemic heart disease
  • 20% to stroke
  • 23% to heart attack

For 2008 provincial and national mortality tables, go to Statistics Canada.

Cost of cardiovascular diseases

Heart disease and stroke costs the Canadian economy more than $20.9 billion every year in physician services, hospital costs, lost wages and decreased productivity (Conference Board of Canada, 2010).

Hospitalizations

The leading cause of hospitalization in Canada continues to be heart disease and stroke, accounting for 16.9 % of total hospitalizations (19.8% of all hospitalizations for men and 14.0% for women) (PHAC, 2009).

In the U.S. (from the CDC)

America’s Heart Disease Burden

  • About 610,000 people die of heart disease in the United States every year–that’s 1 in every 4 deaths.1
  • Heart disease is the leading cause of death for both men and women. More than half of the deaths due to heart disease in 2009 were in men.1
  • Coronary heart disease is the most common type of heart disease, killing over 370,000 people annually.1
  • Every year about 735,000 Americans have a heart attack. Of these, 525,000 are a first heart attack and 210,000 happen in people who have already had a heart attack.2
  1. CDC, NCHS. Underlying Cause of Death 1999-2013 on CDC WONDER Online Database, released 2015. Data are from the Multiple Cause of Death Files, 1999-2013, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. Accessed Feb. 3, 2015.
  2. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-322.

New Theory on Atherosclerosis: Massively Calcified Endosome Death

Larry Weisenthal, M.D., Ph.D.  announced in July 14 (here in an article in “Today’s Practitioner: Advancing Integrative Care” the following:

“New (unpublished) findings may lead to a better understanding on the cause of atherosclerosis. Dr. Weisenthal, a physician and researcher, says he discovered a previously unknown biological mechanism that accounts for vascular calcification. Dr. Weisenthal has named the new mechanism MCED (pronounced EM-sed), or Massively Calcified Endosome Death. He feels that by addressing MCED, it should be possible to stop vascular calcification from occurring, even among individuals with high cholesterol.

“Cholesterol levels probably won’t matter,” says Dr. Weisenthal, “at the end of the day the most important cause of arterial blockage may be the presence or absence of circulating MCED factors.”

According to his report, Dr. Weisenthal discovered that, under some circumstances, artery-forming cells (endothelial cells) die in a unique way that involves the release of highly calcified micro-particles. These escape from dying endothelial cells and trigger the body’s normal immune response. This causes inflammation within the blood vessel and narrows the opening through which blood flows. He contends that MCED is the cause of arterial inflammation.

Exposure of endothelial cells to non-specific toxins or other physical stresses induces death by traditional apoptotic and non-apoptotic mechanisms, common to most different types of cells. In contrast, exposure of endothelial cells (but not other types of nucleated cells) to specific insults, such as oxidized pathogenic lipids (e.g. 7-ketocholesterol) or agents with known anti-angiogenic activity (e.g. bevacizumab, certain tyrosine kinase inhibitors, etc.) triggers cell death via a novel pathway, which involves the formation of massively calcified endosomes, which, in turn, escape from the dying endothelial cells as massively calcified exosomes.

He reports that his laboratory experiments show certain chemicals such as cholesterol can cause MCED to occur – but not in everyone. Blood drawn from different persons varies widely in the ability to prevent MCED from occurring. Experiments showed that sera obtained from different patients vary widely in the ability to support or inhibit MCED.  This may account for the wide variance of risk for atherosclerotic vascular disease which is known to exist among patients whose clinical risk factors are otherwise ostensibly identical.

Isolating the inhibitory factor(s) from sera and/or from endothelial culture media may point the way to the development of pharmaceuticals which prevent and/ or treat atherosclerotic vascular disease. He says it is not yet certain if a single inhibitory factor, multiple inhibitory factors, or some combination of inhibitory and stimulatory factors are involved.  He believes that once the MCED promoters and/or inhibitors have been identified and isolated, pharmaceuticals that either mimic, enhance, or abrogate their activity can be developed.

“That’s the importance of this work,” says Dr. Weisenthal, “It answers the most important questions relating to the genesis of atherosclerosis and identifies the target for specific drugs to prevent and treat it.” Importantly, only endothelial cells are subject to this particular form of cell death. No other cell Dr. Weisenthal has tested can be made to die in exactly this way.”

Source: Massachusetts Newswire

There has been recent controversy in the medical literature and the mainstream media with the suggestion coming forward that calcium supplementation may cause deposition in the arteries

(such as from the article below from Today’s Practitioner)

Should Physicians Stop Prescribing Calcium Supplements?

Calcium supplements should be a thing of the past, says Ian R Reid, MD, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Reid says use of calcium supplements came about when there were no other effective interventions for the prevention of osteoporosis and was based on the belief that increasing calcium intake would increase bone formation. Current understanding suggests this does not occur (though calcium does act as a weak antiresorptive). In the J of Bone Metabolism, author Ian Ried suggests: “In sum, there is little substantive evidence of benefit to bone health from the use of calcium supplements. Against this needs to be balanced the likelihood that calcium supplement use increases cardiovascular events, kidney stones, gastrointestinal symptoms, and admissions to hospital with acute gastrointestinal problems. Thus, the balance of risk and benefit seems to be consistently negative.” Published in the J of Bone Metabolism, Feb. 2014, Ian Ried.

This article is however a good example of how selective study designs may not take into consideration other parameters which may totally change the results and conclusions reached: because it ignores the importance of the interrelationship between compounds such as calcium with magnesium and Vitamin K2 (and others) for optimizing bone health.

A good article on this topic was published in the August, 2012 edition of Life Extension Magazine

However it is reasonable to speculate as to whether Dr. Weisenthal’s findings have any potential impact on this discussion regarding calcium supplementation and CVD.

Of course with any discussion related to health issues we need to take into consideration what key SNPs might influence the development of CVD in our patients: here are a couple of links detailing this information.

http://www.snpedia.com/index.php/Heart_disease

http://www.eupedia.com/genetics/heart_disease_snp.shtml

This information brings up a good point: it is complex and difficult to try to determine how to develop a therapeutic protocol based on this information.
This is exactly the reason why we have been working for the past year to put together a series of educational events which are designed to enable you to incorporate into your practice a Genomics component to enhance your ability to provide  Individualized Health Care.

Genomics Training Update

For this upcoming event we have been working to develop and deliver this Biotics Canada event in close collaboration with the Boucher Institute of Naturopathic Medicine  as well as Dr. Helen Messier, PhD, MD, CCFP, a Vancouver based Functional Medicine MD (certified and on faculty with IFM – the Institute of Functinal Medicine) who also has expertise in applying genomics testing results using a Functional Medicine model in clinical practice.
More information will be forthcoming (and we are in the process of confirming CME accreditation with some of the professional provincial boards) , however we can now confirm the following dates:

Vancouver: October 22

Calgary: October 23

Toronto: October 24

There are several alternative hypotheses (with good supportive research) in existence with respect to the etiology of CVD in addition to the commonly held one (and of course we are not referring to cholesterol which finally seems to be increasingly called into doubt i

n both the medical literature as well as the understanding of the general public: but of course traditional standards of practice take a long time to shift).

It is probably safe to assume that with any complex health issue like CVD, they tend to be more complex than we realize, and probably to some extent both these hypotheses are at least partially relevant: and there are probably issues of importance that we do not even know about yet (as we have witnessed recently with for example the influence of SNPs on health issues or another good example would be what we have learned about the microbiome the last several years).

Here is one hypothesis which is intriguing:

The Myogenic Theory of CVD

Dr. Thomas Cowan, MD, who practises integrative medicine and has a strong affiliation with the Weston A. Price  Foundation wrote a couple of good article on this topic which appear on the Weston A. Price website.
Here is Dr. Cowan’s brief overview: we have included the full articles at the end of our newsletter.

The Myogenic Theory

Briefly, the myogenic theory of MIs states that:

  1. The coronary obstruction theory does not adequately explain all the observed facts concerning MIs.
  2. The major etiologic (cause and effect) factor in an MI is a destructive chemical process; specifically, in situations of stress on the myocardial (heart muscle) tissue, often as a result of small vessel disease, the myocardial tissue gets insufficient oxygen and nutrients. This leads to destructive lactic acidosis in the tissue which, if unchecked, leads to death of the myocardial cells. This process is largely unrelated to coronary artery disease.
  3. The regular use of cardiotonics, primarily low-dose whole digitalis extracts or an extract of another herb called g-strophanthin, prevents this lethal acidosis and therefore prevents and corrects the true cause of this syndrome. The result is substantially lower morbidity and mortality from heart disease.

We have included the links to Dr. Cowan’s two articles at the end of the newsletter.

The Unified Theory

(paraphrased from Linus Pauling’s Unified Theory and Therapy for Heart Disease )

This article and additional supportive documentation is included at the end of this newsletter)

Back in 1989, Linus Pauling and his associate, Dr. Mathias Rath, MD came out with a hypothesis that specific non-toxic substances called Lp(a) binding inhibitors taken orally will prevent and may even dissolve existing atherosclerotic plaque build-ups.

This work is based on at least 2 Nobel Prizes in Medicine and the efforts of countless medical researchers. The theory and conclusions offered represent the final contribution of an American scientific giant.

The fact that you have not heard about this discovery in the mainstream media is disturbing. It speaks volumes about how powerful interests can somehow suppress vital information that would be detrimental to their financial interests.
In 1989, the eminent American scientist Linus Pauling and his associate Matthias Rath MD, unlocked a medical mystery.

They found the reason human beings suffer heart disease.

Then in 1991, Linus Pauling invented a non-prescription cure. The twice Nobel prize winning genius, chemist, and medical researcher made the strong (and so far unreported) claim that heart disease can be controlled, even cured, by a specific “mega-nutrient” therapy.

Heart patients using the Pauling Therapy routinely avoid angioplasty and open heart surgery. Not by lowering cholesterol, as the media would have us believe, but by attacking the root cause. Rapid recovery has been the rule, not the exception. Strangely, there are no known adverse side effects, yet the medical profession ignores Pauling and Rath.

The Pauling and Rath theory relies on this observation that plaque does not form randomly throughout the blood stream

What causes the stress fractures in the walls of blood vessels that leads to heart disease?

The Pauling/Rath unified theory blames a lack of a specific protein caused by a specific vitamin deficiency. Visualize a garden hose being continually stepped on 70-80 times per minute. A fate similar to the coronary arteries feeding the heart. Like the garden hose, the arteries lose their strength and stability over time from wear and tear.

According to Pauling, the atherosclerotic plaques of coronary heart disease form only after cracks or stress fractures appear. This healing process begins with one very important “sticky” form of cholesterol.

What is Lp(a) and why is it important?

Lipoprotein(a) “small a” or Lp(a) is a variant of the so called “bad” LDL cholesterol. Lp(a) is “sticky” substance in the blood that Pauling and Rath believe is the lipid that begins the process of forming atherosclerotic plaques in heart disease. The 1985 Nobel prize in medicine was awarded for the discovery of the cholesterol binding sites. The so-called Lysine Binding Sites. We now know that it is Lp(a) and not ordinary cholesterol which binds to form plaque.

Briefly, Lp(a) has lysine (and proline) receptors. Once Linus Pauling learned that Lp(a) has receptors for lysine, he knew how to counter the atherosclerosis process chemically.

His invention, the Pauling Therapy, is to increase the concentration of this essential and non-toxic amino acid (and proline) in the blood serum.

Lysine and proline supplements increase the concentration of free lysine and proline in the blood. The higher the concentration of the free lysine (and proline) in the blood, the more likely it is that Lp(a) molecules will bind with this lysine, rather than the lysine strands that have been exposed by cracks in blood vessels, or the other lysine that has been attracted to the Lp(a) already attached to the blood vessel wall.

According to Pauling, a high concentration of free lysine can destroy existing plaques.

It is important to keep all this in perspective using the Pauling/Rath Unified theory. If you are not getting enough vitamin C to produce collagen, and your blood vessels are wearing down, then the Lp(a) plaque is of great benefit to you. Simply removing plaque without restoring the vein or artery to health is like tearing a scab off a wound. You do not want to remove the scab until after the tissue underneath has started healing. Your body needs sufficient vitamin C so your veins and arteries can heal.
The Unified Theory blames mechanical stresses (high blood pressures, stretching and bending, etc.) on the blood vessels for exposing lysine that Lp(a) is attracted to. This explains why plaque doesn’t always form. Atherosclerosis is a healing process. Like a scab, plaques form after a lesion or injury to the blood vessel wall.
There is an awesome elegance that these binding inhibitors (vitamin C/lysine) are completely non-toxic.

They are also the basic building blocks of collagen. The unified theory blames poor collagen production for the entire problem of heart disease. Therefore, the Pauling Therapy not only melts plaque, but it attacks the root cause by stimulating the bodies’ production of collagen.

With enough collagen, arteries remain strong and plaque free.
The Pauling and Rath theory postulates that the root cause of atherosclerotic plaque deposits is a chronic vitamin C deficiency which limits the collagen our bodies can make.

So in essence, Heart Disease can be considered a chronic scurvy state.
“I think we can get almost complete control of cardiovascular disease, heart attacks and strokes by the proper use of (vitamin C and lysine) … even cure it.”

From Linus Pauling’s Last Interview

Linus Pauling’s Unified Theory and Therapy for Heart Disease

Robert Lamberton Consulting

Functional Medicine Consultant: Biotics Research

Certified Light/Darkfield Microscopy Nutritionist

Contributing Writer / Advisory Board Member:

Nutricula: The Science of Longevity Journal 

Healthy Organic Woman Magazine

Email: Rob@BioticsCan.com

 

frequently-asked-questions

Medical Marijuana.ca

 

Frequently Asked Questions

1. Where will I obtain my medication from after March 31, 2014? You will be able to choose from your choice of approved Licensed Commercial Producers (LCP). Newly approved producers are added as Health Canada approves them. You can find the complete list of licensed producers at the following link:

http://www.hc-sc.gc.ca/dhp-mps/marihuana/info/list-eng.php

2. What will the cost of my medication be with a Licensed Commercial Producer? Each producer will be setting their own pricing. Patients can expect to spend about $7-$12 per gram. Several licensed commercial producers do have compassionate pricing models for patients receiving disability or assistance payments.

8. Can I travel with my prescription? You may travel with your medication within Canada. You are allowed to carry with you your daily limit x 30 not to exceed 150g.

For air travel it is recommended that you check with the airline. You CANNOT travel outside of Canada with your prescription.

CHFA Responds to CBC Marketplace – Drugstore Remedies: Licence To Deceive

March 13, 2015 By CHF

After extensive consultation with experts and consumers across the country, The Standing Committee of Health decided in 1998 that natural health products (NHPs) are neither foods nor drugs. Based on this, a regulatory system was built which respects Canadians’ freedom of choice, cultural diversity and traditional use of NHPs. This pre-market approval process has positioned Canada as a global leader in the regulation of NHPs, and recognizes applying a pharmaceutical standard is inappropriate for this class of product.

The Canadian Health Food Association (CHFA) agrees the primary objective of Health Canada should continue to be managing the risks to Canadians using the most appropriate level of oversight for different products rather than a “one-size-fits-all” approach.

The evidence requirements for NHPs are risk-based and reflect the low risk nature of these products. Evidence is assessed by Health Canada in order to ensure it supports the claim being made on the product label.

The Canadian “pre-market” regulatory approach requires manufacturers and distributors of NHPs to submit a product’s supporting evidence, health claims, ingredients and labelling to Health Canada before the product is licensed for sale in Canada.

CHFA wants to reassure Canadian consumers that they should be confident all NHPs licensed for sale in Canada, as identified on the label, are regulated by Health Canada under the Natural Health Products Regulations which follow a strict protocol to ensure consumer safety.

CHFA fully supports the Natural Health Product Regulations as a means to ensure Canadians have access to NHPs that are safe, effective and of high quality; this includes vitamins, minerals, probiotics and herbal remedies.

CHFA believes Canadians should continue to have access to NHPs that respect the traditional and cultural beliefs and practices that have been in place, in some cases, for thousands of years. It is also important to acknowledge the role that health care practitioners play in the oversight and management of Canadians’ usage of NHPs.

All NHPs that have been reviewed and approved by Health Canada for sale in Canada have an 8-digit Natural Product Number (NPN). Each licensed product has a unique NPN, like a barcode, which is found on the product label. Additional information is also publicly searchable on Health Canada’s Licensed Natural Health Products Database, including ingredients, recommended use and references.

Health Canada Refines The MMPR Approval Process

By   Posted January 12, 2015   In Industry

Much speculation has surrounded the apparent ‘lag’ in approvals from Health Canada for the better part of last year. After a relative flurry of approvals in late 2013 and early 2014 leading up to the Allard Injunction, Health Canada handed out 13 different license to producers perfectly spaced across Canada and then suddenly appeared to stop for over 7 months.

While this may have left the more compulsive page-refreshers among us a little disappointed, this didn’t mean the regulatory agency wasn’t still inspecting and approving. To the contrary, Health Canada had been busy most of last year re-inspecting those 13 already-approved (surprise as well as scheduled inspections have become routine) and refining their approval process for all LP’s moving forward.

While the approval process pre April 1 may have seemed at times somewhat arbitrary, or at least made in a rush, the new approval system seems to seek to address the shortcomings their initial approach brought on. Now, instead of being given a License to Cultivate and that being the final hurdle to selling (not counting further inspections, renewals, etc), producers have had to seek approval in phases or stages.

Now, after their final facility inspection, a producer is given phase 1 approval, allowing them to grow out a crop, harvest, process, package and store it for future shipment. Passing this phase or stage means you now can have a License to Sell, placing you on the list of 15 others currently licensed to sell. Some have referred to this process in 3 stages, separating ‘Cultivation’ and ‘Production’. This has now reportedly been advanced to requiring two full crops be grown out in phase 1.

This seeks to address some of the issues some early-licensed producers ran into, such as product shortages, recalls, etc. By requiring producers to grow out a full crop and then store it, they are ensuring producers have product on hand as soon as they are able to sell, meaning fewer patients having to wait weeks or months on a ‘waiting list’ as their producer refines their growing process.

LP Process (2)

By splitting this into phases, it allows the regulatory agency to better help pinpoint potential errors in the production line; ensuring a crop is healthy at the point of storage to ensure a producer has a chance to troubleshoot issues that have created problems for other producers without experimenting on their clients in the process. It also helps ensure Health Canada is less likely to find themselves in a position where they have to demand or request a recall from bacterial contamination or simple procedural errors.

Since this new process can take many months, it meant that no ‘new’ approvals were being seen on Health Canada’s list. If a producer was selected for a license to cultivate after April 1 of last year, they were still likely 6 months away from full License to sell. For example, Aphria as well as Maricann both recieved their license to grow in Late spring 2014, and weren’t given final approval to sell until late fall.

Now that Health Canada have now updated their list to note both Cultivators and Sellers, the general public is able to see 5 other producers who are already in possession of a license to grow and likely have been for at least a few months, if not much longer (at least one company currently on the License to Grow list has been there since March 2014). It also notes 3 others with licenses to produce who likely won’t be seeking a license to sell, but rather grow to supply an existing LP (Agripharm, Prairie Plant Systems and Tweed Farms). It doesn’t note a change from phase 1 to phase 2.

So while it may look like Health Canada was doing nothing for most of 2014 in terms of moving the MMPR forward, behind the scenes we see quite a bit of activity, both proactively enforcing rules via inspections and recalls, as well as refining their rules to avoid problems that had been arising. As more producers currently on the Licensed to Cultivate list move up to the Licensed to Sell, we will be seeing companies entering the market with at least 50-100kg on hand, and several other crops quickly behind. This helps increase patient options and competition, but ensures these options are more ready to handle the challenge of consistently serving patient needs when specific strains or cannabinoid profiles are eagerly needed.

Canada: Exporting Dietary Supplements from the US to Canada: A Canadian Perspective

Last Updated: September 2 2014

Article by Albert Chan, Yolande Dufresne and Eileen McMahon

 Manufacturers and distributors intending to market their U.S. dietary supplements in Canada will want to understand the key differences between the regulation of dietary supplements in the U.S. compared to their regulation in Canada.

Introduction

Dietary supplements, which are classified as foods in the U.S., are typically classified as drugs in Canada, and are therefore subject to greater regulatory attention.

Under the Dietary Supplements Health and Education Act, dietary supplements are defined by reference to their ingredients: specifically, whether the product contains a “dietary ingredient” that is intended to supplement the diet, including vitamins, minerals, herbs or other botanicals, amino acids, enzymes, organ tissues and metabolites.1 Dietary supplements may be formulated as tablets, capsules or powders, but may also take more “food-like” forms such as drink and energy bars. Since these products are regulated as foods, manufacturers are not required to submit evidence of safety or efficacy to the FDA before products go to market.

Conversely, with the exception of a few specific products,2 most products classified as dietary supplements in the U.S. would be classified as natural health products (NHPs) in Canada.3 NHPs are regulated as drugs in Canada, although under a different regime than classic prescription drugs. The Natural Health Product Regulations apply to NHPs, whereas the Food and Drug Regulations apply to prescription drugs. NHPs are defined as products containing specified natural ingredients, such as vitamins, minerals, amino acids, or plant, algal, bacterial, fungal, or non-human animal materials or extracts, which are intended for use in: (a) diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state; (b) restoring or correcting organic function; or (c) modifying organic functions.4

The database of licensed NHPs demonstrates the variety of different products approved as NHPs in Canada. In addition to products such as vitamin tablets that would be classified as dietary supplements in the U.S., additional products are regulated as NHPs in Canada, including certain anti-dandruff shampoos, toothpastes, mouthwashes, antiperspirants, and antiseptic ointments and lotions, depending on both the ingredients of the products and the marketing claims made about those products.

Since NHPs are regulated as drugs, the marketing and sale of these products in Canada requires site license approval for a manufacturer and/or importer, as well as license approval of the product itself. Submission of evidence satisfying product safety, efficacy, and quality is generally required. Further, after licensing, NHP manufacturers and importers are subject to continuing regulatory obligations relating, for example, to labelling and marketing, record keeping and reporting of adverse events.

As a result of this more rigorous regulation, however, dietary supplements sold in Canada may be allowed to make more drug-like marketing claims, such as claims to the treatment or prevention of particular diseases or conditions (provided these claims are within the scope of the product’s Canadian NHP license).

NHP Licensing

In practice, product safety and efficacy are handled differently by the U.S. and Canadian regulatory systems for dietary supplements. In the U.S., there is no pre-approval requirement, and the FDA must demonstrate that a product is unsafe before it may take action to remove the product from the market. Conversely, in Canada, the manufacturer or importer must demonstrate to Health Canada that the product is safe, effective, and of sufficient quality before a license will be issued and the product can be marketed for sale.

As mentioned above, a site license is required to manufacture, package, label or import an NHP for sale in Canada5. A site license may be required, for example, even if an importer immediately ships the product to retailers after entry into Canada without first storing the product.6 To obtain a valid site license for a particular NHP, an entity must submit Quality Assurance Reports for both the import site and for any foreign manufacturing sites to demonstrate compliance with Good Manufacturing Practices (GMP). Site licenses will only be granted for domestic Canadian sites; therefore, the NHP license holder is responsible for ensuring GMP compliance of a foreign manufacturer.

In addition to site licensing, Health Canada also requires NHPs to be licensed before marketing and sale in Canada.7 In order to streamline the licensing process, Health Canada has published monographs for ingredients that are commonly found in NHPs. These monographs list previously approved doses, administration methods, indications and claims that can be made with respect to a particular ingredient. Applications for NHPs that conform to the specifications of existing monographs can generally receive approval without further safety and efficacy data. Currently, Health Canada has established three target timelines for responding to NHP licensing applications, depending on the complexity and novelty of the application. Applications indexed against a single ingredient monograph will be reviewed and licensed within 10 days. Applications indexed against multiple monographs are targeted for review within 30 days.

Finally, applications with higher uncertainty, such as those with previously unlicensed claims for serious conditions, never-before reviewed ingredients or combinations, or products with safety concerns are targeted for review within 180 days.8

Health Canada takes a risk-based approach to evaluating safety and efficacy.9 The level of risk associated with an application will depend on the medicinal and non-medicinal ingredients, as well as the recommended use and proposed health claims. Products that bear claims to treat, cure, or prevent serious diseases will attract a higher risk classification, while products directed at general health maintenance or which are directed at minor symptoms or diseases will attract a low-risk classification.

The minimum standard of safety and efficacy evidence depends on the risk categorization of an application. For low-risk products, references to human in vivo data in reputable textbooks regarding medicinal and non-medicinal ingredients may suffice. For high-risk products, Health Canada may require clinical trials.10 Health Canada will also consider positive decisions regarding health and efficacy from other regulatory agencies; however, this may be of limited assistance to exporters of U.S. dietary supplements as licensing approval for these products is not required to enter the U.S. market.11

Labelling

Health Canada requires NHPs to carry specific information on inner and outer labels, reflecting their status as drugs.12 The labels must include medicinal and non-medicinal ingredients, lot numbers, expiry dates, and recommendations for use, including dosage, frequency, and route of administration. A description of the source of each medicinal ingredient must also be provided. Information on labels must be consistent with the information provided in the NHP licensing application, and labels cannot include claims beyond the scope of the license granted by Health Canada.

Certain text on labels must be provided in both English and French, including recommendations for administration, dosage and duration of use, risk information and known adverse reactions, medicinal and non-medicinal ingredients, and appropriate storage conditions.13 his text must be bilingual regardless of whether or not the product is sold in Quebec. If the product is sold in Quebec, additional French language requirements apply, including fully bilingual text and equal prominence of French and English text.14

Post-Licensing Product Changes

Health Canada must be notified if changes are made to the product after licensing. For minor changes with no significant impact on safety, efficacy or quality, Health Canada must be notified within 60 days of the change. Where changes may impact safety, efficacy or quality, Health Canada must approve the change through an amendment to the product license before it is implemented. In cases of fundamental changes to the product, Health Canada may require that a new license be issued, based on fresh supporting evidence of safety, efficacy and quality. Also, if Health Canada changes an ingredient monograph that is related to an NHP, the manufacturer or importer must submit either a notice of change or proposed amendment, depending on the impact of the change to the monograph.15

Adverse Event Reporting

As with prescription drugs, NHP licensees must report adverse events to Health Canada. Under the NHP Regulations, individual case reports must be sent to Health Canada within 15 days for each serious adverse reaction that occurs in Canada, and for each serious and unexpected adverse reaction domestically or internationally. Further, Health Canada requires annual reports to be prepared compiling all adverse reactions inside Canada and individual case reports as required above.16

Advertising of NHPs in Canada

Advertising for drugs in Canada, including NHPs, may be reviewed by Advertising Standards Canada (ASC), a self-regulatory body of the Canadian advertising industry. Although there is no legal requirement to submit proposed advertisements to ASC for review, as a practical matter, the majority of print and broadcast media outlets will not run advertisements without ASC approval. Although ASC is independent from Health Canada, it will review advertisements for compliance with Health Canada regulations.17 ASC will generally provide a review within four business days for a nominal fee, and will grant an ASC approval number that can then be provided to media outlets.

For television advertising, manufacturers and importers should also seek approval from the Television Bureau of Canada (TVB), a non-profit association that operates on behalf of the major Canadian television broadcasters, meaning that without TVB approval, the avenues for television advertising may be limited. Costs for review and approval of advertising by TVB are paid by member television broadcasters, with reviews generally provided within one to three business days, and same-day review available for a nominal fee. Each version of a television advertisement should receive its own review and approval from TVB.

Unintentional Export

If a dietary supplement is not marketed or sold in Canada, and there is no intent to export the product to the Canadian market, U.S. manufacturers and distributors should still understand the implications of cross-border “spillover” of the product. Generally speaking, Health Canada has taken the position that where there is no intent to export and no marketing or sales operations are active in Canada, domestic Canadian drug regulations would not apply.18 Further, individuals are permitted to cross the border with a three-month personal supply of a dietary supplement that has not been approved for sale in Canada, since this amount is regarded as insufficient for commercial sales.19 However, Health Canada has issued blanket prohibitions on the import of particular products and ingredients into Canada. Health Canada regularly issues recalls and press releases regarding particular NHPs that contain prohibited or toxic ingredients. A current list of product recalls, alerts, and advisories may be found on the Health Canada website.20

Conclusion

Because of the differences in classification of dietary supplements as foods in the U.S. and NHPs (a class of drug) in Canada, any manufacturer who seeks to export a dietary supplement to Canada will want to be aware of applicable Canadian regulations.

Originally published by FDLI’s Update.

Footnotes

1. 108 Stat. 4325.

2. In some circumstances, if the dietary supplement is in a particularly food-like form, is packaged and represented as a food product, and is perceived by the public as a food product, Health Canada is may classify a dietary supplement a food. Health Canada’s policy, for example, is to classify energy drinks as foods: (http://www.hc-sc.gc.ca/fn-an/legislation/pol/energy-drinks-boissons-energisantes-eng.php).

3. Natural Health Products Directorate, Food Directorate, Classification of Products at the Food-Natural Health Product Interface: Products in Food Formats (June, 2010); Health Canada, Foods Marketed as Natural Health Products, online (http://www.hc-sc.gc.ca/fn-an/prodnatur/index-eng.php).

4. Natural Health Products Regulations, S.O.R./2003-196, s. 1 [NHP Regulations].

5. NHP Regulations, supra note 4 s. 27.

6. NHP Regulations, ibid; see Natural Health Products Directorate, Site Licensing Guidance Document, (September 2007), online (http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodnatur/slgd-drle-eng.pdf).

7. NHP Regulations, supra note 4 s. 4; see Natural Health Products Directorate, Pathway for Licensing Natural Health Products Making Modern Health Claims, (December 2012), online (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/modern-eng.php) [Licensing Pathway]; see also Natural Health Products Directorate, Pathway for Licensing Natural Health Products used as Traditional Medicines, (December 2012), online (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/tradit-eng.php).

8. Health Canada, The approach to natural health products, online (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/nhp-new-nouvelle-psn-eng.php).

9. Licensing Pathway, supra note 7.

10. Ibid.

11. Ibid.

12. NHP Regulations, supra note 4 s. 86; see Natural Health Products Directorate, Labelling Guidance Document, (August 2006), online (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/labelling-etiquetage-eng.php) [Labelling Guidance]; see also Health Canada, Labelling Requirements Checklist, (April 2011), online (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/label-list-etiquet-eng.php).

13. NHP Regulations, supra note 4 s. 87; Labelling Guidance, supra note 12.

14. Charter of the French Language, C.Q.L.R. c. C-11, s. 51.

15. NHP Regulations, supra note 4 ss. 11-13; see Natural Health Products Directorate, Post Licensing Guidance Document, (December 2007), online (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/plgd_psdldr-eng.php).

16. NHP Regulations, supra note 4 s. 24; see Health Canada, Guidance Document for Industry – Reporting Adverse Reactions to Marketed Health Products, (2 March 2011), online (http://www.hc-sc.gc.ca/dhp-mps/pubs/medeff/_guide/2011-guidance-directrice_reporting-notification/index-eng.php).

17. see e.g. Health Canada, Guidance Document: Consumer Advertising Guidelines for Marketed Health Products (for Nonprescription Drugs including Natural Health Products), (18 October 2006), online (http://www.hc-sc.gc.ca/dhp-mps/advert-publicit/pol/guide-ldir_consom_consum-eng.php).

18. see Health Products and Food Branch Inspectorate, Import and Export Policy for Health Products Under the Food and Drugs Act and its Regulations, POL-0060, (1 June 2010), online (http://www.hc-sc.gc.ca/dhp-mps/compli-conform/import-export/pol-0060_biu-uif-eng.php).

19. Ibid.

20. Online (http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/index-eng.php?cat=5).

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

 

The Canadian Supplement Marketplace and Regulations for Dietary Supplements

Article by – Peter Wojewnik

The U.S. economy is expected to grow by only 2.9 percent in 2010. With this subpar expansion and the recent recession, many dietary supplement companies have started to expand their businesses in foreign markets. Canada appears to have become a hot target. “This past year we’ve seen our client base change from about 25 percent U.S.-based companies to well over 50 percent,” reported Alicja Wojewnik, president of dicentra, a Canadian scientific and regulatory consulting firm.

The attraction of the Canadian marketplace is not surprising. Nutrition and supplement use is an everyday part of Canadian lives. Currently, 71 percent of Canadian adults report they have used a natural health product, and 38 percent report they use at least one on a daily business. With a population roughly one-tenth the size of the United States, setting foot in this marketplace could easily result in 10-percent sales growth.

Entering the Canadian market, however, is not easy. Unlike the U.S. regulatory landscape, where dietary supplements are monitored post-market, Canada requires products to be licensed prior to market entry by the Natural Health Products Directorate (NHPD), a branch of Health Canada. Years ago, supplements required no pre-market approval and consumers raised concerns over the safety, efficacy and quality of these products. As a result, in 2004, Health Canada established the Natural Health Products Regulations and the NHPD to address these concerns. “Prior to 2004, companies simply created a product, slapped on a compliant label and went straight to market,” said one regulatory expert. “Today, however, the requirements are much more rigorous and many companies are having difficulties meeting these requirements.” As a testament to this, since 2004, the NHPD has completed its review of about 33,000 of 43,000 applications submitted. Out of these, 48 percent have either been withdrawn or refused.

To date, companies have been “lucky” when it comes to enforcement due to a backlog of applications at the NHPD. When the regulations came into place in 2004, the NHPD received an influx of tens of thousands of applications and has not been able to clear this queue of applications since. As a result, enforcement has been minimal and only high-risk products have been targeted. Examples of products considered to be high risk include those intended for children or pregnant women. Although it is a legal requirement to have a product license to sell a supplement in Canada, with the backlog and without a performance standard in place, the NHPD has minimized enforcement measures on products being sold with a submission number. A submission number is a number issued by the NHPD several weeks after a Product License Application has been submitted for review that acknowledges a complete application has been received and placed in queue. The NHPD, however, has been improving its performance and the backlog is quickly clearing. Later this fall, the directorate is expected to make an announcement on new enforcement measures with potential target dates as to when products will absolutely require a license before entering the marketplace.

For U.S. companies importing products into Canada, the situation is different. The American-Canadian border is an easy place to employ enforcement measures. Every shipment of product entering the country can be inspected to ensure compliance. Customs agents spot-check shipments to verify supplements are in queue at the NHPD and possess a submission number. Without a submission number, products are turned away. There is also another element to the equation. “In addition to the requirement for a product license, NHPs (dietary supplements) must be manufactured, packaged, labeled and imported in accordance with the NHP GMPs (good manufacturing practices),” said William Morkel, dicentra’s senior quality assurance and regulatory affairs advisor. Any domestic company involved in any of these activities must apply for and be issued a Site License by the NHPD. This means U.S. companies’ products must be brought into the country by a domestic importer that holds a valid Site License to import supplements.

There are, therefore, two unconditional requirements for U.S. companies entering the Canadian marketplace. One is a submission number for each product, and the second is an importer on record with a valid Site License. “If the foreign manufacturer is not annexed onto the Site License of the domestic importer and if the product itself does not have a submission number and/or represents a high risk, it is likely that the shipment will be refused entry into Canada,” Morkel said. It is also important to keep in mind that sooner than later, a submission number will not be enough and a product license will be required for entry. It is crucial, therefore, for any companies considering expanding to Canada to take special care in ensuring each of their products has a thorough application in queue with the NHPD.

In addition to an upcoming announcement this fall from the NHPD for potential target dates for enforcement, there is pressure being felt from retailers as well. Regardless of what compliance measures will be taken against unlicensed products in the future, there is no question retailers are developing a strong preference for licensed products. To retailers, licensed products represent less risk compared to those without a license. As a testament to this philosophy, the Order of Pharmacists of Quebec and the National Association of Pharmacy Regulatory Authorities have recently recommended to all pharmacies across Canada not to sell supplements without a product license as of Jan. 1, 2010.

It is clear bringing a product to the Canadian market is no easy task, and it is only expected to become more difficult when new enforcement measures are put into place. The benefits, however, continue to outweigh these obstacles. The Canadian supplement industry at retail level is expected to exceed $2.75 billion in value by the end of 2010, and as consumers become more aware of the stringent regulatory requirements in place, their confidence in these products will grow and sales will only continue to increase. What’s more, Canada’s regulatory model is being recognized by the international community and products licensed by Health Canada are being looked upon favorably by markets abroad. Many American companies have recognized this opportunity and have begun to take charge of the Canadian marketplace.