Latest information for:
|• Chronic Fatigue Syndrome (8)||• Fibromyalgia (8)||• Diet and Nutrition (1)|
|• Depression (2)||• Immune System (2)|
Chronic Fatigue Syndrome
- Which CFS Patients Should We Treat With Anti-Viral Medicines? (2015)
- Can A Probiotic Help Treat Chronic Fatigue Syndrome? (2015)
- Rituximab: A Potential Medical Treatment for Chronic Fatigue Syndrome (2014)
- Chronic Fatigue Syndrome Causes Inflammation in the Brain (2014)
- AAHC, A Natural Immune System Booster (2014)
- Increased Gene Activity Proves CFS and FMS are Physical and Real (2014)
- Maitake Mushroom: Another Natural Immune System Booster (2014)
- Can the “Mind Diet” Reduce “brain fog” due CFS and Fibromyalgia? (2015)
- Melatonin Helps Fibromyalgia Pain (2015)
- Dry Needling Plus Physical Therapy a Major Advance for Fibromyalgia Treatment (2015)
- Namenda: A Potential New Treatment for Fibromyalgia (2015)
- Low Dose Naltrexone (LDN): Possibly a Major Conceptual Breakthrough (2014)
- Coenzyme Q Improves Fibromyalgia Pain and Fatigue (2014)
- Increased Gene Activity After Fatiguing Exercise Proves CFS and FMS are Physical and Real (2014)
- MRI Imaging Proves that Fibromyalgia is "Real" 2012
- Can the “Mind Diet” Reduce “brain fog” due CFS and Fibromyalgia? (2015)
Diet and Nutrition
- Can the “Mind Diet” Reduce “brain fog” due CFS and Fibromyalgia? (2015)
- Methyl-folate, A Natural Add-on Treatment for Severe Depression (2015)
- An Effective Natural Anti-Depressant With Relatively Few Side Effects (2014)
- AAHC, A Natural Immune System Booster (2014)
- Maitake Mushroom: Another Natural Immune System Booster (2014)
Which CFS Patients Should We Treat With Anti-Viral Medicines?
Several prominent CFS specialists have been treating selected patients with Valcyte (valacyclovir), an anti-viral drug directed against herpes class viruses such as Epstein-Barr Virus (EBV) and Human Herpes Virus-6 (HHV-6). Their anecdotal experience has been favorable. However, the entire CFS-ME-Valcyte literature contains only rigorously controlled double-blind study.
The senior author is Jose Montoya, M.D., professor in the division of Infectious Disease at Stanford Medical School. The study’s results are encouraging but are far from conclusive—at least in part because the study’s “N” is rather small. But, what makes me optimistic is the fact that despite the study’s limitations, Dr. Montoya has continued to treat CFS-ME patients with Valcyte. A co-author, Andy Kogelnik, M.D., who practices in Mountain View, California, also continues to use Valcyte. Both highly regarded experts are convinced that Valcyte can help a meaningful subset of patients.
In 2006, the Stanford group reported treating twelve CFS-ME patients with Valcyte for 6 months. These encouraging results persuaded Roche to help fund a double blind trial. The study: twenty patients received Valcyte for six months; ten took placebo. To qualify subjects had to have very high IgG antibody levels against both EBV and HHV-6.
The primary end point was a 20 question self-report questionnaire, the MFI-20. (The MFI-20’s questions are included among the supplemental information on the Wiley download.) The MFI-20 answers were analyzed in two distinct ways. One method used standard statistical analysis. The other asked four blinded physicians to review the same MFI-20 data. The physicians were asked to decide which among the 30 subjects had improved significantly. The statistical method, it turns out, gives only mild encouragement for using Valcyte, but the physicians’ judgment was more optimistic.
Using standard statistical methods the total MIF-20 score documented a non- significant improvement with Valcyte compared to placebo. (P=.114). In contrast, the blinded physicians’ interpretation judged that subjects treated with Valcyte were 7.4 times more likely than those on placebo to have been “responders”. (P=.029). Also encouraging: The MFI-20 contains a subgroup of questions that focuses on mental/cognitive fatigue. The mental /cognitive scale, when analyzed by itself, did show significant improvement for those taking Valcyte. (P=.039). A secondary end point, the Fatigue Severity Scale (FSS) also showed a significant improvement in cognitive functioning but only non-significant improvement in physical function.
When I first read the study I was confused. How could the blinded physicians find so much more improvement compared to the standard statistical analysis? Dr. Montoya was kind enough to discuss these and other issues with me. Dr. Montoya believes that the blinded physicians probably felt that the answers to the mental/cognitive questions were clinically more important than those of the other MFI-20 questions. Based on his clinical experience Dr. Montoya believes that the MFI-20 physical scores might have been limited by the clinical fact that when CFS-ME patients feel better, they tend to increase their activity. This tends to increase their level of physical fatigue.
Side effects: Valcyte is FDA approved to treat Cytomegalovirus (CMV) in the context of HIV or organ transplants. In these populations serious side effects are very frequent. In contrast, in the CFS-ME study, Valcyte “was well tolerated and was not discontinued due to hematologic or hepatic events.” That Valcyte seems to be much better tolerated in the CFS-ME population is a critical issue as we decide whether or not we should use it to treat patients.
Other key points: Dr. Montoya’s clinical impression is that treatment longer than six months gives better results than the six month cut-off used in the Study. He has seen substantial improvement after treating for one year even among patients who had not improved at six months. Dr. Montoya’s current monitoring includes CBC, CMP, urinalysis and a physician visit at baseline and then monthly. He no longer requires weekly labs during the first month. He currently starts with Valcyte at 450 mg daily for the first 2 to 4 weeks and then 450 mg bid. In the study, they used 900 mg bid initially and then reduced to 450 mg bid.
Dr. Montoya noted that many patients get worse during the first month or two of treatment. Unless the worsening is severe or sustained, he continues treating typically for one year. An informed consent for Valcyte treatment should include the fact that Valcyte can cause cancer in animals, although it is not known whether Valcyte increases cancer risk in humans. Please note: CFS by itself has been associated with increased risk of lymphoma. Epstein-Barr virus has been associated with lymphoma and other cancers. So, at this time we don’t really know if Valcyte treatment for CFS-ME would decrease, increase or not affect long term cancer risk.
The patients in this study all had very high antibody IgG levels against both EBV and HHV-6. This very high antibody group probably includes only about 15-20% of the CFS-ME population. Treating patients with lower antibody levels has not been studied. A practical problem for physicians in the U.S. Insurance plans may be reluctant to approve paying for Valcyte as a treatment for CFS-ME. Best to seek approval from a physician supervisor.
We all recognize that very high antibody levels provide only a rough guess as to which patients are more likely to respond to anti-virals. What we need but don’t yet have is a validated lab test that identifies which patients have reactivated virus versus those who have high antibodies due to inactive, latent infection. We also recognize that it would be best to repeat the Valcyte double blind study with a larger number of patients. But, things being as they are, research funds for our “orphan illness” are not yet high priority. For the time being we have to make judgments with the limited information we have.
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IMPORTANCE: Prior to this review of the literature and discussions with Dr. Montoya and Dr. Kogelnik, I had not been willing to treat with Valcyte. Too toxic for little benefit, I thought. Now I am persuaded that Valcyte probably can help a substantial number of patients. I will soon start offering it to selected patients—assuming I can convince the insurance plans to cover it.
Initial study abstract: www.ncbi.nlm.nih.gov/pubmed/17276366.
Roche abstract: www.ncbi.nlm.nih.gov/pubmed/23959519. To view the full article via Wiley Publications for free, select the "Full Text Link" from the abstract page.
Can A Probiotic Help Treat Chronic Fatigue Syndrome?
The focus is on a commercially available species of probiotic called Bifidobacterium infantis 35624. Proctor and Gamble sells this product under the brand name Align. Natren sells a different but closely related B. infantis species.
Substantial animal and test tube research suggests that certain Bifidobacterium species can suppress and/or increase inflammatory markers (1-4). Recently, an Irish research group from University College in Cork fed high doses of the B. infantis 35624 strain versus placebo to 48 subjects who had Chronic Fatigue Syndrome. After 8 weeks persons taking the probiotic had significantly reduced levels of 3 inflammatory markers compared to levels observed with placebo. These markers were CRP, Interleukin 6 and Tumor Necrosis Factor Alpha.
Researchers did not evaluate the course of clinical symptoms for these patients. So, we don’t know whether or not clinical symptoms also improved. (Anecdotally, in a similar study of patients with psoriasis, one of the investigator’s “impression” was that clinical improvement also occurred.) This raises several questions. Can the improvement in the 3 inflammatory markers be confirmed? What happens to other inflammatory markers such as IL17? Do clinical symptoms improve? Would other species of Bifidobacteria be as effective? Who might fund further clinical studies?
The subjects of this double blind trial included 48 patients with CFS. Diagnosis was based on the Center for Disease Control Criteria. There were also 22 patients who had ulcerative colitis and 26 with psoriasis. Researchers measured the blood levels for three inflammatory mediators: C-reactive protein (CRP), Tumor Necrosis Factor alpha (TNF-alpha) and Interleukin 6 (IL-6). At baseline all three inflammatory markers tended to be higher among patients compared to healthy controls.
Subjects took one packet daily containing either ten billion colony forming units (cfu) of B. infantis 35264 or a placebo. For CFS and psoriasis patients the study lasted 8 weeks. For Ulcerative Colitis patients, the duration was 6 weeks. (Please note that B. infantis 35264 is available under the brand name Align. The dose used in the Irish study was 10 billion colony forming units daily. Align comes in capsules of one billion cfu.)
The Results: For all three diseases CRP levels declined significantly among subjects taking the probiotic compared to those taking placebo. For chronic fatigue syndrome the P value was 0.0285. The majority of CFS patients showed a decrease in their CRP. For Tumor Necrosis Factor Alpha, levels declined with probiotic compared to placebo for subjects with CFS and for Psoriasis. TNF alpha did not decline for patients with ulcerative colitis. For CFS P=0.0214. For Interleukin 6, levels were significantly lower among CFS patients fed probiotic compared to placebo (P=0.054). IL-6 declined significantly with B. infantis compared to placebo for ulcerative colitis. IL-6 did not decline significantly among patients with psoriasis.
Did the patients who were took B. infantis 35624 tend to feel better than those on placebo? I emailed the lead author, Dr. Quigley and he confirmed that his group did not collect data on clinical outcomes. To do so would have required a considerably more expensive study.
Critical Question Addressed to All Readers: Does anyone know a high executive at Proctor and Gamble—the producer of the Align brand of B. infantis 35624? Align has supported several clinical studies. If their product truly helps CFS, psoriasis and or ulcerative colitis that could certainly expand their product. Or might another strain of B. infantis also be effective, e.g. B infantis sold by Natren?
Open Question: Should clinicians who treat ME/CFS offer patients the option of take a B. infantis product based despite limitations of current evidence? Pro: As interventions go, adding a probiotic is relatively safe. Taking B. infantis is not likely to cause any major harm. If a significant number of patients with ME/CFS report improvement to their doctors, that information might create support for a double blind study. (Or should we ask for postings to a prominent ME/CFS website such as ProHealth.com, Phoenix Rising (http://phoenixrising) or to ME-Global Chronicle? Cons: One small double blind study without clinical end points isn’t much to go on. Also, please note that the dose used in this study (10 billion cfu) is ten times higher than the dose in one capsule of Align (one billion CFU). Currently Target sells forty two capsules of Align each with one billion cfu for about $37. So a 68week trial of 10 billion cfu would cost about $300.
Another concern: My understanding is that Dr. Quigley’s group developed the B. infantis 35624 strain, and then licensed it to Proctor and Gamble, who now sells it as Align. I’ll guess that the Irish group treated their subjects with freshly made probiotic. This would have maintained its initial potency. Commercially available Align, in contrast, might have sat on shelves for many months. Its potency when taken is likely to be much less than one billion cfu per capsule. For example, one point that has always been prominent in Natren’s marketing is that they ship fresh product and keep it on ice.They guarantee it’s potency.
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IMPORTANCE: My tentative take on what I think we have learned: Bifidobacteria infantis 35624 at 10 billion cfu per day taken for 8 weeks tends to reduces three markers of systemic inflammation, CRP, TNF alpha, and IL-6. Please note: this conclusion has two parts. One: B. infantis 35624 has anti-inflammatory actions. Two: these anti-inflammatory effects are not limited to the gut—where probiotics live. Rather they affect the body systemically.
The Key Article: Greoger, D…..Quigley, M., Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut, Gut Microbes, 2013, 4(4):325-339. Abstract: www.ncbi.nlm.nih.gov/pmc/articles/PMC3744517.
Underwood, M…Dvorak, B, Bifidobacterium longum subsp. Infantis in experimental necrotizing enterocolitis: alterations in inflammation, innate immune response and the microbiota, Pediatr Res, 2014;76:326-33.
Rodes L, Saha, S, Tomaro-Duchensneau C, Prakash S, Microencapsulated Bifidobacterium longum subsp. Infantis ATCC 15697 favorably modulates gut microbiota and reduces circulating endotoxins in F 344 rats, Biomed Res Int 2014:602832. Doi: 10.1155/606832 E pub 2014
Whorwell P, Do probiotics improve symptoms in patients with irritable bowel syndrome? Therap Adv Gastroenterol 12009; 2:37044.
Tanabe S, Kinuta Y, Saito Y, Biforbacterium infantis suppresses proinflammatory interleukin-17 production in murine splenocytes and dextran sodium sulfate-induced intestinal inflammation, Int J Mol Med 2008;22:181-5.
Ewaschuk, J….Madsen K, Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function, Am J Physiol Gastrointest Liver Physiol 2008; 295:G1025-34.
Rituximab: A Potential Medical Treatment for Chronic Fatigue Syndrome
Norwegian researchers randomized 30 patients with CFS to treatment with either placebo or Rituximab. Rituximab suppresses the B cell branch of the immune system. B cells are the part of the immune system that makes antibodies.1
In this double blind study, 10 of 15 CFS patients treated with Rituximab had substantial improvement. Most improved to the degree that could be called a “remission”. In the placebo group 2 of 15 patients improved. This difference was highly significant statistically (p=.003). The odds of this difference occurring by chance were very small—only 3 in 1000.
But, there’s a catch—actually, several.
It took months after treatment for the remissions to come about. Most remission lasted only about six months, although at least one patient has been well for more than one year.
The researchers speculate that the Rituximab may have suppressed a clone of immune cells that were producing harmful antibody. This would have led to a slow decline in antibodies and then a remission. As the B cell system recovered, the bad antibody returned and with it the CFS. At least one patient was treated a second time, and a second remission was obtained.
The big problem is this. By suppressing the immune system, Rituximab can increase risk for serious even fatal infection. Therefore, for now, Rituximab may be too toxic to use.
IMPORTANCE: This is the first study to show convincing evidence that CFS can be put into remission. Might this lead to a cure for chronic fatigue syndrome? Is CFS an auto-immune disease? Are there safer autoimmune drugs that could give the same benefit as Rituximab? We will need funds for more research in order to find out. (posted September 5, 2012)
1Øystein Fluge, et al. Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study, PLoS One. 2011; 6(10): e26358. Abstract: www.ncbi.nlm.nih.gov/pubmed/22039471.
Chronic Fatigue Syndrome Causes Inflammation in the Brain
For most people with Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) central nervous system function is clearly abnormal. However, we don’t understand the mechanisms involved. Many experts suspect an inflammatory component, but cytokine studies of cerebrospinal fluid have yielded uncertain results.
Now, researchers at the RIKEN Center for Life Science Technologies in Hyogo, Japan, have directly measured neural inflammation using a combination of PET scan and MRI imaging. Their key findings: Compared to healthy controls, nine patients with CFS/ME showed evidence of abnormal activation of microglia and/or astrocyte immune cells within the brain. In specific brain areas the degree of immune activation correlated closely with the severity of the patients’ symptoms.
Positron emission tomography (PET) is a nuclear medicine technique that produces a three-dimensional image of physiological processes within the body. PET works by attaching a gamma ray emitting tracer to a biological molecule that is normally processed by specific cell types. Appropriate computer software then constructs a three-dimension image of the tracer’s concentration. A concurrent MRI or CT scan further defines the anatomical locations.
The tracer for this study (called 11-C-(R)-PK111995) attaches to a specific translocator protein called TSPO. When microglia or astrocytes are metabolically active TSPO is expressed. PET scan imaging of TSPO is a standard technique for studying inflammation in neurological disorders. For the nine patients in this study the intensity of PET imaging was substantially higher among the CFS/ ME patients compared to controls in the following brain areas: The cingulate cortex, hippocampus, thalamus, mid brain and pons.
Equally impressive, there was a high correlation between the TSPO image intensity and the severity of the patients’ reported symptoms. For example, the peak value signal within the left thalamic intralaminar nucleus was highly correlated with the cognitive impairment score. (r=0.86; P=0.0028) and also with the patients’ intensity of fatigue (r=0.63; P=0.0683). If further studies confirm these findings, we should be asking the following questions: 1) Why are the brain’s immune cells inflamed? Is there an on-going infectious process? Did an initial but no longer active insult trigger sustained inflammation? Is the inflammation responding to other nervous system damage e.g. over-activity of neurons to compensate for the functional limitations caused by CFS/ME? 2) Would it be useful (or harmful) to treat using drugs or natural products to suppress neuro-inflammation?
As a clinician I’ll focus on the second question. Standard anti-inflammatories such as ibuprofen and prednisone do not help CFS/ME. However, other anti-inflammatories work through quite different pathways. Might these be worth trying? For example, low dose naltrexone (LDN) is believed to have a “calming” effect on brain microglia cells. Two double blind studies from Stanford Medical School show improvement in Fibromyalgia symptoms with LDN treatment.
The tetracycline derivatives Minocycline and Doxycycline have well recognized anti-inflammatory effects. Colchicine, and pentoxyfilline can act as anti-inflammatories. Quite a few herbs do as well including curcumin, panax ginseng, green tea, resveratrol, Gastrodia, and Ginger. None of these have been systematically tested for CFS/ME. All could be considered to be “relatively” safe.
In contrast, Rifaximab, a powerful and potentially toxic B cell suppressor has one double blind study from Norway that demonstrates a statistically significant advantage over placebo in dramatically reducing the symptoms of CFS. Fortunately, the investigators were then able to obtain funds to see if they could replicate their excellent results. This study is currently under way. Unfortunately, in the USA and most other countries CFS/ME remains an orphan disease. So it’s not likely that we will see double blind studies testing other anti-inflammatories for CFS/ME any time soon. Until we know for sure should CFS/ME clinicians selectively offer (with proper informed consent) empirical treatment with anti-inflammatory medicines or herbs?
Key Reference: Nakatoni, Y…Watanabe, Y, Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11 C-R-PK11195 PET Study, J Nucl Med published on March 24, 2014 as dol:10.2967/jnmed.113.131045. Abstract: www.ncbi.nlm.nih.gov/pubmed/24665088.
Naltrexone and Fibromyalgia: Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014 Apr;33(4):451-9. doi: 10.1007/s10067-014-2517-2. Epub 2014 Feb 15. Abstract: www.ncbi.nlm.nih.gov/pmc/articles/PMC3962576.
Natural Products and Microglia: Choi, D, Koppula, S, Suk, K, Inhibitors of Microglial Neurotoxicity: Focus on Natural Products, Molecules, 2011, 16, 1021-43l diu =L 19,3390/molecules 1602021. Abstract: www.ncbi.nlm.nih.gov/pubmed/?term=inhibitors+microglial+natural++focus
Rifaximab and chronic fatigue syndrome: Øystein Fluge, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study.PLoS One. 2011;6(10):e26358. doi: 10.1371/journal.pone.0026358. Epub 2011 Oct 19.
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AAHC, A Natural Immune System Booster —Can it Help Fight CFS?
What causes Chronic Fatigue Syndrome? A leading theory is that the immune system has become weak, allowing reactivation of latent Herpes Class Viruses such as Epstein-Barr, HHV-6, Herpes Simplex, CMV and/or other micro-organisms. Think of Shingles being caused by a reactivation of latent chicken pox virus.
Logically, anti-viral drugs should be more effective if the immune system is more competent. And if the immune system were strong, perhaps it could control these infections on its own, without adding anti-viral drugs. A key article introduces a natural product called AHCC (active hexose correlated compound). AHCC derives from Shitake mushroom. Like Reishi mushroom and the pharmaceutical, Imunovir, AHCC has proved immune activating effects in animals. However, human studies are limited.
Should we offer AHCC or similar immune boosters to our patients? Should we offer AHCC as a primary treatment and/or as an add-on to antiviral drugs such as Valcyte, Valtrex or Famvir?
Our Key Research Article: In cancer patients Japanese researchers tested whether adding AHCC to cancer chemotherapy decreased adverse effects due to cancer chemotherapy. Twenty four patients with various cancers received their first weekly dose of standard chemotherapy without adding AHCC. One week later they received their second dose along with oral AHCC. End points included standard blood tests, a quality of life questionnaire and a post-chemo therapy quantitative measure of DNA in the patient’s saliva due to Herpes Virus 6 (HHV-6). HHV-6 is a Herpes class virus.
Compared to the first chemotherapy dose done without AHCC the second dose (with AHCC) gave the following results. With AHCC:
- Quality of Life Scores were significantly higher.
- Blood toxicity and Liver toxicity rates were significantly lower.
- DNA levels of HHV-6 in the saliva were significantly lower.
The authors concluded: 1) AHCC may have a beneficial effect on chemotherapy-associated adverse effect 2) HHV-6 DNA levels in saliva may be a good biomarker of immune system status and 3) that AHCC might have partly countered the immune-suppressing effects that normally occurs with cancer chemotherapy.
Adapting these results to CFS, it is tempting to speculate that AHCC might improve the immune system’s ability to control reactivated viral or bacterial infections. We can’t take this single study too far. But, it should focus our attention on potential clinical trials and/or empirical treatment for CFS using immune-strengthening agents such as AHCC, Reishi or Imunovir.
AHCC has a considerable in vitro and animal literature supporting its immune boosting and anti-viral effects. AHCC’s toxicity profile seems favorable, but with this theoretical caution. By over-activating the immune system AHCC might do harm if autoimmune issues are a problem.
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IMPORTANCE: AHCC, a Shitake mushroom derivative is an effective immune system booster and anti-viral agent in animal systems. The Key article suggests it might have similar benefits in humans. It should be considered as a possible adjunctive treatment for patients with CFS.
Increased Gene Activity Proves CFS and FMS are Physical and Real
University of Utah scientist, Dr. Alan Light and colleagues asked 48 patients with CFS/FMS to peddle a stationary exercise bike for 25 minutes. Over the next 48 hours they measured the output of messenger RNA derived from 13 pre-selected genes. These genes involve the immune system, nerve signaling, and inflammation.1
Before exercise messenger RNA output was the same for CFS/FMS patients as for healthy persons who served as controls. After exercise healthy controls reported no fatigue and had no significant changes in their output of messenger RNA. In contrast, for most CFS/FMS patients messenger RNA from these genes increased dramatically after exercise and remained abnormally high for 48 hours. This confirmed the patients’ reports of clinical pain and fatigue.
IMPORTANCE: If confirmed, Dr. Light’s messenger RNA test provides objective proof of a physical mechanism causing the post-exertional flare up of symptoms that often occurs with both chronic fatigue syndrome and severe fibromyalgia. (Posted September 5, 2012)
1Light, A et. al. Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. J Intern Med. 2012 Jan;271(1):64-81. Abstract: www.ncbi.nlm.nih.gov/pubmed/21615807.
Melatonin Helps Fibromyalgia Pain
Melatonin is popularly used as a sleeping pill—although it likely helps only a small proportion of patients. But, surprise! Several double blind studies suggest that Melatonin might also combat Fibromyalgia pain. One study found that Melatonin improved pain due to temperomandibular joint disorders (TMD) 1. Another showed benefit for pain caused by endometriosis 2. Now, a double-blind study from Brazil suggests that high dose Melatonin taken regularly for six weeks probably reduces Fibromyalgia pain 3.
This optimistic conclusion is tentative, since there was no true placebo group in this study. Rather, Melatonin was as or possibly more effective than Elavil (amitryptiline), a medicine which has long been used to treat Fibromyalgia. Take-Home Lesson: despite, the lack of placebo, Melatonin’s relative safety suggests that physicians might consider a trial of Melatonin for their Fibromyalgia patients.
The KEY STUDY: Sixty three women with Fibromyalgia were randomized to receive either 25 mgs of amitriptyline or 10 mgs of Melatonin or amitryptiline and melatonin together. All doses were given at bedtime. Patients kept diaries starting at baseline and through the six weeks of the study. They recorded the time and intensity of the worst pain they experienced during each 24 hour period. Intensity was scored using a Visual Analogue Scale where zero means no pain and 100 means the worst possible pain. Although patients in all three groups had less pain after six weeks than they did at baseline, patients receiving Melatonin alone or Melatonin plus amitryptiline had significantly lower pain scores than patients who received amitryptiline alone. (P<.01). Patients receiving amitryptiline alone scored about 12 points lower at six weeks compared to baseline. Those taking Melatonin alone were about 17 points lower. Those taking Melatonin plus amitryptiline were about 18 points lower.
Quality of Life was measured using the Fibromyalgia Impact Questionnaire. This questionnaire asks about symptoms and the ability to function in ten different areas e.g. the number of days that the person was not able to work. Again, all three groups improved. Improvement was greatest for those taking both amitryptiline and Melatonin. Improvement was second best for those taking Melatonin alone and least for those taking only amitryptiline.
Researchers also measured each patient’s average pain pressure threshold (PPT) at baseline and again after six weeks. To measure PPT, increasing pressure was applied until the patient stated that the pressure began to hurt. Pain pressure threshold improved for all groups. Improvement was greater for those taking Melatonin alone or with amitryptiline. Those taking Amitryptiline alone also improved, but less so than the other groups. Sleep quality improved by about the same degree in all three groups.
The bottom line is that improvement in pain due to Melatonin alone and/or Melatonin and Elavil together was significantly better than that obtained by treatment with Amitryptiline by itself. The strength of this study is that the effect of Melatonin was compared to amitryptiline , a medicine that is generally believed to have a positive effect on reducing Fibromyalgia pain. The study’s main weakness reflects the lack of a true placebo control group. Despite the fact that almost all Fibromyalgia specialists believe amitryptiline is useful, there have been surprisingly few double blind studies done to test this belief4. Could all or most of the improvement in all three groups have been a placebo effect? Not likely in my opinion, but not impossible.
For now I think it’s wise to assume that Melatonin is fairly likely to be useful. And because side effects from Melatonin are only rarely a problem, a trial of treatment with Melatonin with or without amitryptiline might be considered. BUT, this study’s use of Melatonin was not typical of the way most people use Melatonin. When taken to treat jet lag or to induce sleep, Melatonin is usually taken for only a few days or only intermittently. In contrast, the Brazilian study gave Melatonin every night for six weeks. Pain levels were reported only during the baseline period and at the end of six weeks. So anyone using Melatonin to help Fibromyalgia pain should be prepared to take it every night for six weeks before judging whether or not it helps.
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As important, the dose used was quite high, 10 mgs each night. For jet lag people usually use a dose of 0.5 mg. To induce sleep doses of 1 mg, 3 mg or 5 mg are common. And while Melatonin at lower doses is almost always safe, we have almost no published experience about long term experience with high doses as high as 10 mgs. Hopefully, other groups will find funding enough to do further controlled studies on Melatonin for Fibromyalgia. Such studies, I expect, would include a true placebo arm. But, until then, let’s be grateful for the Brazilian group’s efforts.
1Vidor LP, et al, Analgesic and sedative effects of melatonin in temporomandibular disorders: a double-blind, randomized, parallel-group, placebo-controlled study.J Pain Symptom Manage. 2013 Sep;46(3):422-32. doi: 10.1016/j.jpainsymman.2012.08.019. Epub 2012 Nov 27. Abstract: www.ncbi.nlm.nih.gov/pubmed/23195393.
2Schwertner A, Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial. Pain. 2013 Jun;154(6):874-81. doi: 10.1016/j.pain.2013.02.025. Epub 2013 Mar 5.. Abstract: www.ncbi.nlm.nih.gov/pubmed/?term=schwernter+melatonin+endometriosis
3T Azevedo de Zanette et al, Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in Fibromyalgia: a phase II, randomized, double-dummy, controlled trial. BMC Pharmacology and Toxicology 2014, 15:1-14.. Full article: www.biomedcentral.com/2050-6511/15/40
4 Moore RA1, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for fibromyalgia in adults., Cochrane Database Syst Rev. 2015 Jul 31;7:CD011824. doi: 10.1002/14651858.CD011824.. Abstract: www.ncbi.nlm.nih.gov/pubmed/26230384
Dry Needling Plus Physical Therapy: A Major Advance for Fibromyalgia Treatment
Dry needling is a technique used by specially trained physical therapists, physicians, and dentists to help treat several forms of musculoskeletal pain. Developed and popularized by Janet Travell, M.D. , David Simons, M.D and colleagues during the 1950s and 1960s 1, controlled studies have shown benefit for regional myofascial pain2, temperomandibular joint dysfunction (TMD) 3, and chronic tension headache4. It typically uses an acupuncture type needle to enter into and disrupt localized spots of intense muscle spasm called trigger points. This may allow almost immediate relaxation of the involved muscle. This often relieves pain. It also allows concurrent physical therapy to be done more effectively. The needling is called “dry” because no medicines are injected. Several studies show that dry needling alone is as effective as injecting a local anesthetic or corticosteroids into the trigger point.5
Three years ago, the New Jersey State Board of Physical Therapy authorized physical therapists to treat with dry needling. Since the excellent physical therapy group I refer to added dry needling to their tool kit, their results for my Fibromyalgia patients have greatly improved. Today I’m pleased to report on a double blind study from Spain that confirms the benefits from adding “dry needling” to standard treatments.6
Researchers from the Rheumatology Services at the Specialist Clinic of Cantabria in Santander, Spain added six weekly one hour sessions of dry needling to the standard treatment of 60 Fibromyalgia patients. Another 60 patients (controls) continued with standard treatment alone. Unlike the usual practice of inserting needles into palpable trigger points within any symptomatic muscle, the Santander group inserted their needles specifically into the site of the 18 standard Fibromyalgia tender points. These anatomical locations were defined by the American College of Rheumatology.7 Clinically, we find the standard tender point sites often also contain trigger points.8
After six weeks of treatment the patients treated with dry needling improved considerably more than the control patients who did not have dry needling. Several measures of pain and fatigue status showed major benefit. Improvement was found for each of the following: The Visual Analogue Scale for Pain (P=0.002), the Visual Analogue Scale for Fatigue (p=.02), the SF-36 health questionnaire (p=.0001), the degree of pain elicited by pressing six specified sites with a dolorimeter (pain inducing device )(p=0.0005), the amount of pressure needed to induce pain (p=.002) and a survey of global subjective improvement (P=.00001). (The P values indicate the probability that the advantage of dry needling was due to chance. A P value of .05 or greater is considered to be statistically significant. A P value of .01 or greater is highly significant.)
No dry needling was done during the next six weeks. Then outcomes for both groups (treated and controls) was measured again. Most impressively, six weeks later—12 weeks after the study started—the advantage for the dry needling group over the controls, continued to be high.
Now for the “bad” news. In the United States, although dry needling by physical therapists is authorized in about half the states, only a modest number of physical therapists, physicians or dentists have major experience with dry needling. For many Fibromyalgia patients the simplest way to locate a trained or experienced practitioner will be contact the programs that train clinicians in this technique. They can refer you to their graduates. They also might know other experienced clinicians. As with any therapeutic technique training and experience are important. Serious complications are rare with experienced clinicians.9 However, untrained or novice practitioners are not likely to be as effective or as safe.
In the Northeast United States the main training program is run by Robert Gerwin, M.D., a professor of neurology together with Jan Dommerholt, PT, PhD, an outstanding physical therapist.10 I have personally taken courses with this group as have the physical therapist I most often refer to Painpoint.com and myofascialpaintreatment.com/about-tp-dry-needling/.
Is dry needling related to acupuncture? Except that both use a similar tool, the theory and practice of dry needling have little in common with acupuncture. They are fundamentally different. A few acupuncturists have also trained in dry needling. Unfortunately, a guild mentality may have developed among acupuncture organizations. In New Jersey and several other states, the acupuncture professional society is attempting to ban physical therapists from doing dry needling on the grounds that dry needling by physical therapists is the “illegal practice of acupuncture”. Good grief.
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IMPORTANCE: Dry needling done alone without concurrent physical therapy is more likely to relapse if posture, weak or tight muscles remain. The best results should occur if dry needling and physical therapy are done at the same time.
1Travel, J and Simons, D, Travell & Simons' Myofascial Pain and Dysfunction: The Trigger Point Manual: Two Volume Set: Second Edition/Volume 1 and First Edition/Volume 2: 2nd Edition Lippincott Williams & Wilkins.
2 Tsai, C, Remote effects of dry needling on the irritability of the myofascial trigger point in the upper trapezius muscle. Am J Phys Med Rehabil. 2010 Feb;89(2):133-40. Abstract: www.ncbi.nlm.nih.gov/pubmed/?term=tsai+dry+needling.
3THE KEY ARTICLE: Fernández-Carnero J et al, Short-term effects of dry needling of active myofascial trigger points in the masseter muscle in patients with temperomandibular disorders. J Orofac Pain. 2010 winter;24(1):106-12. Abstract: www.ncbi.nlm.nih.gov/pubmed/20213036.
4France S, et al. Evidence for the use of dry needling and physiotherapy in the management of cervicogenic or tension-type headache: a systematic review, Cephalgia 2014 (12):994-1003. Abstract: www.ncbi.nlm.nih.gov/pubmed/?term=france+dry+needling.
5Venancio R de A et al. Different substances and dry-needling injections in patients with myofascial pain and headaches., Cranio 2008 26:96-103. Abstract: www.ncbi.nlm.nih.gov/pubmed/?term=different+substances+and+dry+needling.
6Casaneueva, b et al. Short-term improvement following dry needle stimulation of tender points in fibromyalgia, Rheumatol Int (2014), 34: 861-6. Abstract: www.ncbi.nlm.nih.gov/pubmed/23609584.
7Wolfe et al, The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee, Arthritis Rheum. 1990 Feb;33(2):160-72.
8Gerwin, R, Fibromyalgia tender points at examination sites specified by the American College of Rheumatology criteria are almost universally myofascial trigger points, Curr Pain Headache Rep. 2011 Feb;15(1):1-3. Abstract: www.ncbi.nlm.nih.gov/pubmed/20978951.
9Brady S et al, Adverse events following trigger point dry needling: a prospective survey of chartered physiotherapists, J Man Manip Ther 2014 11(3): 234-40. Abstract: www.ncbi.nlm.nih.gov/pubmed/25125935.
10Dommerholt J. Dry needling - peripheral and central considerations, J Man Manip Ther. 2011 Nov;19(4):223-7. Abstract: www.ncbi.nlm.nih.gov/pmc/articles/PMC3201653/.
Namenda: A Potential New Treatment for Fibromyalgia
Namenda (memantine) is well established, treatment for moderate to severe Alzheimer’s Disease. Namenda acts to reduce the activity of a set of receptors in the brain and spinal cord called NMDA receptors. Over-stimulation of NMDA receptors is believed to contribute to the increased pain sensitivity in Fibromyalgia. Therefore, treating Fibromyalgia patients with memantine should, in theory, decrease Fibromyalgia pain.
But, for the last decade no one was willing to invest the funds needed to put this theory to the test. Now that has changed. A very capable Spanish research team has done a double blind study. The results: Fibromyalgia patients treated with memantine had less pain, better cognition and better day to day function compared to a control group, who took a placebo. If these results are confirmed by future studies, memantine could quickly become a mainstay choice Fibromyalgia treatment.
The key research study was done in Spain. Subjects who met the American College of Rheumatology 1990 case definition for Fibromyalgia were recruited to take either memantine or a placebo. During the six month trial subjects taking memantine had substantially less pain, improved cognitive ability, and better day to day function than did patients taking a placebo. Statistically significant improvement occurred within the first month and persisted throughout the entire six months long trial.
Memantine’s side effects tend to be mild. There are relatively few adverse interactions with other drug. So, if these encouraging results are confirmed by further studies, Namenda (memantine) could quickly become a mainstay treatment.
Dr. Barbara Olivan-Blazquez , Dr. Javier Garcia-Campayo and their team from Zaragosa University recruited about 60 long term fibromyalgia patients. Half received memantine, the others took a placebo. They measured pain status in two different ways. First, they used a visual analogue scale where patient rate their subjective perception of pain on a scale of zero to ten. Zero means no pain. Ten is the worst pain possible. After one month on memantine, the average visual analogue score decreased from 6.56 to 4.83. That is, the memantine patients reported less pain. In contrast, subjects taking placebo modestly increased their pain score from 6.48 to 6.64. The difference favoring the memantine group was highly significant (P=0.001). Significant differences favoring the memantine group continued throughout the six month long study.
A second way to measure pain was to pump up a blood pressure cuff. At baseline, the memantine group subjects complained of pain when the blood pressure cuff average reading was 97.9 millimeters of Mercury (mmHg). One month later, it required an average blood pressure of 112 mmHg. Before pain was noted. Thus, pain sensitivity had decreased. Patients on placebo showed the opposite—a mild increase in their sensitivity to blood pressure cuff induced pain.
The degree of pain improvement was moderate for most memantine patients, although it was dramatic in a few. Only sixteen percent of the memantine -treated subjects achieved a 50% improvement in pain (5 of 31subjects). BUT none (0%) of the subjects on placebo had that much improvement. Subjects on memantine also did significantly better than those on placebo for the mini-mental status test of cognitive function, on a depression scale and on several measures of functional activity. The bottom line: Subjects taking memantine tended to feel better while also being more active.
Is it reasonable for a physician to consider using memantine as an “off label” treatment for fibromyalgia? We have only one fairly small study. So we cannot say for sure if memantine “really works”. But, as medicines go, memantine is considered to be fairly safe. Among Alzheimer’s patients the most common side effects are dizziness, headache, confusion and constipation. Adverse drug interactions are few. But one should avoid mixing memantine with other NMDA receptor antagonist medicines such as amantadine, ketamine and dextromethorphan (the cough suppressant in Delsym).
The Spanish researchers started treating at 5 mg once daily. They titrated over one month to a final dose of 10 mg twice daily. Since people with fibromyalgia tend to be very sensitive to medicine side effects, I would tend to increase the dose even more slowly until we are sure that the patient tolerates the medicine. The big obstacle I foresee is how to gain funding sufficient to repeat the Spanish study. Memantine is available as a generic. So there may be little incentive for Forest Laboratories (who makes brand name Namenda) or the generic manufacturers to spend the $millions that would be needed to obtain FDA approval for them to promote memantine as a Fibromyalgia treatment. Happily, the Spanish government provided major financial support for the Zaragosa research.
Key Article: Olivan-Blazquez, B…. Garcia-Campayo, J, Efficacy of memantine in the treatment of fibromyalgia: A double-blind randomized, controlled trial with 6-month follow-up. Pain 155 (2014): 2517-2515. Abstract: www.ncbi.nlm.nih.gov/pubmed/25218600. Article: www.biomedcentral.com/content/pdf/1745-6215-14-3.pdf.
Fayed, N…Garcia-Campayo, J, Changes in Metabolites after Treatment with Memantine in Fibromyalgia. A double-blind randomized Controlled Trial with Magnetic Resonance Spectroscopy with a 6-month follow-up, CNS Neuroscience & Therapeutics, 20(2014): 999-1007.
Serra, G, …Kahn, D, Memantine in the Treatment and Prophylaxis of Bipolar II Disorder and Comorbid Fibromyalgia: A case Report, Journal of Psychiatric Practice 20 (2014): 232-6. Abstract: www.ncbi.nlm.nih.gov/pubmed/24847998.
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Low Dose Naltrexone (LDN): Possibly a Major Conceptual Breakthrough
Probably a Useful Treatment for Fibromyalgia Pain
My opinion: Clinicians who treat FM and/or CFS/ME should consider themselves obligated to learn more about LDN and, with informed consent, consider offering it to selected patients.
Naltrexone is an opiate antagonist, FDA approved for a dose of 50 mg. At “normal” doses naltrexone tends to increase pain. But at low doses, in the 3-4 mg range, LDN has long been used by alternative medicine-minded clinicians as a treatment for pain, fatigue and other symptoms. In brief, LDN seems to help a meaningful proportion of FM patients. And, so far, its side effect profile has been relatively benign—almost certainly more favorable than our standard FM drugs. As importantly, LDN’s proposed mechanism—suppression of inflammatory cytokines within the central nervous system might lead toward a new approach for a broad range of diseases.
A key article is from Stanford Medical School’s Division of Pain Management. Jarred Younger PhD, and Sean Mackey, M.D., PhD are the lead authors. Using a double blind design, each of 31 women with Fibromyalgia were treated with either 4.5 mg of naltrexone in the evening for 12 weeks and a placebo for 4 weeks. (Low dose naltrexone was prepared by a local compounding pharmacy.)
Reduction in pain scores compared to baseline were significantly greater during the LDN period compared to placebo. (28.8% reduction versus 18% reduction; P=0.016). LDN was also associated with improved general satisfaction (P=.045) and better mood (P=0.039). Thirty two percent of participants had an improvement in both pain and either fatigue or sleep while on naltrexone in contrast to an 11% response rate during placebo (P=0.05). The #1 “side effect” was increased dreaming, which some subjects felt were disturbing.
Other than a small pilot trial, I believe this is the only academically sound study testing LDN for Fibromyalgia. However, I and at least one other CFS-ME/Fibromyalgia specialist have found LDN useful. (Nancy Klimas, M.D, PhD personal communication). Dramatically exciting is LDN’s proposed mechanism—suppression of pro-inflammatory activity triggered by microglial cells within the CNS. Inflammatory cytokines appear to be increased within the CNS of patients with Fibromaygla, CFS-ME and a broad range of health problems.
Preclinical research indicates that Low Dose Naltrexone can suppress the activity of microglial cells and reduce the production of pro-inflammatory cytokines. Might LDN or other cytokine reducing intervention help patients with Multiple Sclerosis, Parkinson’s or Alzheimer’s? Hopefully, more research will follow—despite the disincentive that naltrexone has long been “off patent”.
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IMPORTANCE: Low dose naltrexone helps relieve pain in a substantial proportion of people with Fibromyalgia. In some people it may also help with fatigue and mood. Not all patients tolerate LDN but the most frequent side effects—increased dreaming and headache—are not dangerous and often decrease over time. Except for people who regularly take narcotics, it is reasonable to consider a trial of LDN.
Coenzyme Q Improves Fibromyalgia Pain and Fatigue
Dr. Mario Cordero, a professor at the University Of Seville Medical School in Spain recently treated Fibromyalgia patients with high dose Coenzyme Q 10 (300 mg) versus placebo. Taken for 40 days Coenzyme Q was much more effective than placebo for improving pain, fatigue and morning tiredness (P<.001).
Coenzyme Q is a powerful anti-oxidant that helps support the function of mitochondrial, the energy producing factors within our cells. Among people with Fibromyalgia mitochondrial energy production is often reduced, in part due to increased oxidative stress. It is generally considered to be safe. So except for the cost, there’s little reason not to try it. However, Coenzyme Q tends to be absorbed poorly.
Having some fat in your stomach at the same time you take Coenzyme Q helps improve absorption. For example, take COQ10 with dinner--usually the fattiest meal--or with a fish oil capsule or with a teaspoon of olive oil. Ubiquinol, an improved form of Coenzyme Q is better absorbed than traditional Coenzyme Q (which is called ubiquinone). Other nutrients that might help mitochondria include: Creatine, Carnitine, Lipoic Acid, NADH (Enada) and Riboflavin (vitamin B2).
IMPORTANCE: We are finally beginning to see a few double blind studies of natural treatments for fibromyalgia, chronic fatigue syndrome and other complex health problems. One single study, such as this, does not prove that a treatment is effective, but it's certainly more encouraging than having no data at all.
Cordero MD, et. al. Can Coenzyme Q Improve Clinical and Molecular Parameters in Fibromyalgia? Antioxid Redox Signal. 2013 Apr 6. Abstract: www.ncbi.nlm.nih.gov/pubmed/23458405.
MRI Imaging Proves that Fibromyalgia is "Real
University of Florida scientist, Robert Staud, M.D. studied persons with fibromyalgia and healthy persons who served as controls. They imaged the brain using an advanced form of MRI called Functional MRI. Functional MRI “lights up” specific pain centers in the brain when these centers become active. 2
Staud applied light pressure to the skin of persons with FMS and to persons who were healthy. For healthy persons light pressure caused no change in brain activity on the Functional MRI image. But heavy pressure made the brain’s pain centers “light up”.
In contrast, for persons with fibromyalgia even light pressure caused pain and caused their brain’s pain centers to become active. Thus, functional MRI imaging confirms the fibromyalgia patient’s typical report that even light stimuli can cause substantial pain.
Dr. Staud states: “Overall, functional brain imaging studies have provided compelling evidence for abnormal pain processing in FMS, including brain activity that correlated with patients' augmented pain sensitivity...”
IMPORTANCE: Functional MRI provides objective proof that fibromyalgia pain is real and that FMS patients report truthfully. (posted September 5, 2012)
2Staud, R, Brain. Imaging in Fibromyalgia Syndrome. Clin Exp Rhematol 2011; 29:S109-17. Abstract available from www.ncbi.nlm.nih.gov/pubmed/22243558
Can the “Mind Diet” Reduce “brain fog” due CFS and Fibromyalgia?
The short answer is we don’t know, because research on “brain fog” has been limited--to say the least.1 Therefore, I hope our readers will be encouraged to learn that a relatively simple diet change is probably effective for reducing or delaying another currently “untreatable” form of brain fog—that due to Alzheimer’s Disease.
For many decades we’ve faced an army of dietary fads. Each has claimed the ability to improve health. But, almost all claims are based mainly on anecdotes. Scientific studies have largely been absent. Fortunately, that’s changing. Controlled studies of the effects of different diets have started to be done.
The best research has focused on the “Mediterranean Diet” as a preventive treatment for heart disease and stroke.2 Researchers recruited more than 7000 Spanish men and women who were at high risk for heart disease or stroke. Using a random decision tree, each person was assigned to follow either a treatment diet or a control diet. The treatment diet was the “Mediterranean Diet” plan (high in unsaturated fats such as olive oil and/or nuts, high in fruits, vegetables and whole grains, but low in saturated fat). The control diet was a standard low fat diet, such as the American Heart Association might advise.
After 5 years, those on the Mediterranean Diet had 30% fewer cardiovascular events (heart attacks, strokes) compared to those on a low fat diet. Statistically, the advantage of the Mediterranean Diet was highly significant. Two points are especially encouraging. The Mediterranean Diet was practical. People stayed on it not just for awhile, but for more than 5 years. As importantly, five years was long enough to reduce the incidence cardiovascular events by 30%. The Mediterranean Diet might also delay or prevent the onset of Alzheimer’s dementia.
About six years after beginning the cardiovascular disease study the Mediterranean Diet researchers selected 522 persons from within the main study and put them through neuro-cognitive testing.3 Since initially these persons had been assigned to each diet at random, if cognitive testing had been done at the beginning of the study (which was not done), likely the initial scores for the two groups should have been roughly equal. What we do know is that after six years the group on the Mediterranean Diet scored significantly higher cognitive testing compared to those in the low fat arm of the study.
The differences favoring the Mediterranean Diet group remained after adjusting for other risk factors including age, sex, education, ApoE genotype, family history of dementia, smoking, physical activity, body mass index, high blood pressure, high cholesterol, and diabetes. This suggests that the Mediterranean Diet, not only prevents heart attacks and stroke, but also helps maintain cognitive skills. But, since baseline cognitive scores were not measured, a true controlled study was still needed.
In 2015 Valls-Pedret and the Mediterranean Diet study group reported the results of a small controlled study. This also supports the ability of the Mediterranean Diet to reduce cognitive decline. 4 The study was done on about four hundred 60+ year old Spanish volunteers who were randomized to follow either a Mediterranean-style Diet or a low fat diet. Cognitive tests took place at the start of the study and again 4.1 years later. After 4.1 years in the study cognitive test and memory scores were higher for the Mediterranean Diet group compared to the low fat diet control group subjects.
Conclusion: Evidence is increasing that the Mediterranean Diet, not only prevents heart attacks and stroke, but likely also helps maintain cognitive skills. Would the Mediterranean Diet also help patients with ME/CFS or FM? Maybe yes; maybe no. But, either way, we can probably reject the long-held “main stream” view that the reported benefits from improving diet is mainly a placebo. That view now seems to be badly outdated.
Further work on diet an Alzheimer’s comes from Martha Morris, Ph.D. and her research team at Chicago’s Rush University Medical Center.5 Dr. Morris’ team may be the world’s leading experts on the effects of nutrition on cognitive decline due to aging. Dr. Morris modified the Mediterranean diet to take into account other research on dementia. She named this the MIND DIET. While there are differences between the MIND and Mediterranean Diets, their basic these are fairly similar.
Dr. Morris and her colleagues enrolled 923 Chicago men and women, age 58 to 98. None had Alzheimer’s at the start of the study. At baseline dieticians analyzed each person’s current eating pattern to compare it with the key principles (which can be downloaded below) of the MIND DIET. Over the next 4.5 years 144 of 923 (16%) of those in Dr. Morris’ study were diagnosed with Alzheimer’s. Participants whose Mind DIET scores were initially in the top third were only 47% as likely to develop Alzheimer’s compared to those in the bottom third. This difference was highly significant statistically (P=.0006). Those in the middle third did better than those in the lowest third, but not as well as those in the upper third.
Dr. Morris also calculated a score measuring how closely each person adhered to a Mediterranean Diet style. Using Morris’ score, the Mediterranean Diet pattern also predicted a low Alzheimer’s rate but not quite as well as did high scores for the MIND DIET. A strength of Dr. Morris’ study was that the statistical analysis controlled for life style behaviors, illnesses and genetic risks for Alzheimer’s. The study’s main limitation is that researchers did not actively assign subjects to each diet. They simply scored how closely each subject’s self-chosen diet compared to the MIND DIET ideal. So, we can’t be sure whether high adherence to the MIND diet caused the lower rate of Alzheimer’s or whether other factors might have been at work.
In a separate paper Dr. Morris’ group calculated that better adherence to a MIND DIET style of eating was associated with slower decline in global cognitive score (P<.0001). The difference in cognitive skills between the top third on the MIND DIET and those in the bottom third were equivalent to the top third being “7.5 years younger in age” compared to the bottom third”—although chronologically in fact their average age was the same.6
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So, which diet should one follow if we have brain fog due to Fibromyalgia or Chronic Fatigue Syndrome? At this time, we have no easy answer. Ideally, someone would fund a study where patients with CFS or Fibromyalgia would take a cognitive test, then go on either the MIND DIET (or Mediterranean Diet) or their usual way of eating. But, things being as they are, that kind of funding isn’t likely to appear.
Next best: if people who adopt the MIND DIET or the Mediterranean on their own report this to their doctors and/or to health support websites such as Prohealth.com. Enough favorable self-reports might be create enough wind to shake a money tree somewhere. For those interested in applying the MIND DIET it might be best to aim for a score of 12 on the MIND DIET index. For those interested in the Mediterranean Diet, consider a book by Nick Nigro and Bay Ewald, Living the Mediterranean Diet: Proven Principles and Modern Recipes for Staying Healthy.
1Ocon, Anthony, Caught in the thickness of brain fog: exploring the cognitive symptoms of Chronic Fatigue Syndrome, Front Physiol. 2013; 4: 63. Published online 2013 Apr 5. DOI: 10.3389/fphys.2013.00063. Abstract: www.ncbi.nlm.nih.gov/pmc/articles/PMC3617392. Correspond with Dr. Ocon at: Anthony_ocon@nymc.edu
2Ramón Estruch, M.D. et. al. for the PREDIMED Study Investigators, Primary Prevention of Cardiovascular Disease with a Mediterranean Diet, N Engl J Med 2013; 368:1279-1290 April 4, 2013. DOI: 10.1056/NEJMoa1200303. Abstract: www.nejm.org/doi/full/10.1056/NEJMoa1200303#t=articleMethods
3Martinez-Lapiseina, et al. Mediterranean diet improves cognition: the PREMIDED_NAVARRA randomized trial. J Neurol Neurosurg Psychiatry 2013:84: 1318-25. Abstract: www.ncbi.nlm.nih.gov/pubmed/?term=mediterranean+diet+improves+cognition
4 Valls-Pedret, C et al. Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial, JAMA Intern Med 2015;175(7): 1094-1-3. Abstract: www.ncbi.nlm.nih.gov/pubmed/25961184.
5Morris, M, et. al MIND diet slows cognitive decline with aging. Alzheimer’s and Dementia, 2015 Jun 15. pii: S1552-5260(15)00194-6. doi: 10.1016/j.jalz.2015.04.011. [Epub ahead of print]. Abstract: www.ncbi.nlm.nih.gov/pubmed/26086182
6Morris MC1 et al, MIND diet associated with reduced incidence of Alzheimer's disease, Alzheimers Dement. 2015 Feb 11. pii: S1552-5260(15)00017-5. DOI: 10.1016/j.jalz.2014.11.009. Epub ahead of print]. Abstract: ncbi.nlm.nih.gov/pubmed/25681666
Methyl-folate, A Natural Add-on Treatment for Severe Depression
Our body requires small proteins called enzymes to drive key steps of biochemical metabolism. Specific genes direct the production of specific enzymes. But, if a gene undergoes a mutation, the enzyme it produces is likely to be physically distorted or misshaped. Such enzymes may be less effective drivers of their relevant biochemical pathways. One example, is the MTHFR enzyme, a key player in folic acid metabolism.
We need the MTHFR enzyme to transform folic acid (a synthetic form of the folate vitamin) into methylfolate, which is the active form of the vitamin (also known as vitamin B9). Folic acid has been added to most commercial grains and most multi-vitamin and B-complex supplements.
Problem: A great many people have mild, moderate or severe distortions of their MTHFR enzyme because of mutations to the specific genes that produce this enzyme. Among 1000 newborn babies in Wisconsin 8% were homozygous for the gene for the MTHFR gene mutation. With such a double dose mutation—one “bad” gene from each parent—the ability to activate synthetic folic acid can be reduced by 60% or more. With a single dose mutation (heterozygous), the MTHFR enzyme might be 30% less efficient. About 30% of the Wisconsin babies had the single dose mutation.
People who eat lots of raw green vegetables don’t have to worry. The form of folate in greens veggies is methylfolate—which is already active. But, many perhaps most Americans don’t eat large amounts of leafy greens. Instead they rely on the folic acid added to breads, cereals and vitamin pills. The result: If you don’t eat a lot of greens AND you have an MTHFR gene mutation, your folate metabolism is liable to be weak. This in turn could compromise your ability to make a broad range of key biochemicals. For example, S-Adenosyl Methionine (SAMe) a natural anti-depressant; also neurotransmitters such as Dopamine, Serotonin, Norepinephrine; also Carnitine, Creatine and others. Lack of active methyl folate may also compromise the ability to repair damage to our DNA.
Medical scientists accept these relationships in principle. But what we don’t know for sure whether the theoretical harm caused by low methylfolate is or is not clinically important. Would taking more methylfolate substantially augment treatment for chronic fatigue syndrome, depression, Alzheimer’s , coronary disease or any other health problems? Animal studies and anecdotal reports on internet sites suggest that it can.
But, I could not find any placebo controlled double blind studies testing whether people with any common diseases AND an MTHFR gene mutation actually do better when treated with methylfolate. That academic researchers have been slow to do expensive double blind clinical trials with methylfolate is not entirely surprising. You can’t patent methylfolate, so pharmaceutical companies are not likely to fund studies. And there’s long-standing ( but hopefully fading) legacy among academics that “natural” treatments border on quackery.
Happily I did find one exception to the absence of controlled clinical research. This was a multi-center study captained by psychiatrists from Harvard Medical School’s Massachusetts General Hospital. Several years ago, the MGH group reported that the natural supplement SAMe (S-Adenosyl Methionine) was superior to placebo for treating patients whose unipolar depression had not responded well to Serotonin Reuptake Inhibitor medicine (SSRI’s). (2) Please recall: you need active methylfolate in order to make SAMe.
In 2012, the Mass General group published a similar study of methylfolate versus placebo. Again the subjects were patients with unipolar depression who remained depressed despite continuing use of an SSRI. The result: A very high dose of methylfolate (15 mg) was superior to placebo within 30 days of treatment. (3, 4) (Please recall that the RDA for folic acid is only 0.4 mg daily or 400 micrograms.) However, a lower dose of methylfolate was not much better than placebo.
In 2014, the MGH team reported further data from their 2012 study. They classified the 2012 study patients according to several clinical parameters and also the mutation status of 16 specific genes that are relevant either to methylfolate metabolism or related methylation pathways. Patients whose initial blood levels of S-Adenosyl Methionine were fairly low were more likely to improve from Methylfolate treatment than were patients whose baseline SAMe levels were fairly high. That’s what we should expect, since methylfolate is required to produce Methionine. Methionine is then converted into SAMe. But, to my surprise, having an MTHFR mutation did not significantly predict a better outcome from methylfolate treatment. But, when an MTHFR mutation was combined with certain other specific mutations, that combination did predict that most of those patients would benefit. Mutations in other methylation genes also predicted benefit from treating with methylfolate.
I hope that the Mass General/Harvard halo will attract other researchers and funding agencies to support clinical studies of methylfolate. not just for depression but also for “orphan” conditions such as ME/CFS. So, where does this leave people who suffer from ME/CFS. I and other ME/CFS specialists recommend testing for the MTHFR mutation. For those who are homozygous or heterozygous, I think it’s justified to have an empirical trial of treatment with a combination of methylfolate together with vitamins B12 and B6—starting at low doses and then working up. At the same time please keep in mind: MTHFR treatment for ME/CFS is not yet well proved.
Cautions: 1) Methylfolate should usually be accompanied by vitamins B12 and B6. If B12 or B6 activity is weak, adding methylfolate could make things worse. result. 2) One patient in the Massachusetts General study developed new symptoms of mania while on methylfolate. Essentially all standard anti-depressants medicines and also SAMe also share this potential risk. If a patient already has a history of mania i.e. bipolar disorder, then most patients should be referred to a psychiatry specialist. 3) Several dozen genes potentially interact with the MTHFR related biochemical pathways. We don’t understand their interactions as well as we might wish. There are very few true experts in this field, and even they quickly admit that they still have much to learn. When multiple gene abnormalities are present side effects from MTHFR –related treatments can become problems.
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An Effective Natural Anti-Depressant With Relatively Few Side Effects: S-Adenosyl Methionine (SAMe)
Patients with chronic illness of any kind are vulnerable to depression. Unfortunately, standard anti-depressant medicines don’t work for everyone. Side effects can also cause problems, especially for people with CFS-ME, who are especially side effect prone.
S-Adenosyl Methionine (SAMe) is a natural product with more than a dozen double blind studies showing benefit for depression. Yet very few physicians in the U.S. know much about it, psychiatrists included. Of course, SAMe can’t be patented, so there’s little commercial incentive to fund physician education. But, it’s also a concern that many of SAMe’s double blind studies have not been of high quality.
Rigorously evaluating SAMe’s effectiveness is important, because, anecdotally, SAMe seems to be effective, seems to interact safely with standard antidepressants, and is definitely less likely than SSRI’s to cause sexual dysfunction. The Psychiatry Department of the Massachusetts General Hospital has now published a double blind study that fairly well proves that SAMe really works. The MGH team enrolled 73 patients with had not improved despite treatment with a Serotonin Reuptake Inhibitor. The investigators continued SSRI treatment but added either SAMe (800 mg bid) or placebo for six weeks of treatment. Using the Hamilton D depression scale 46% of patients on SAMe improved compared to only 30% with placebo. (P<.05) Full remission (HAM- D score <7) occurred among 35.8% of SAMe patients versus only 11.7% of those on placebo. (P=03). (Bizarrely, the Abstract of the published article mistakenly understates the benefit of SAMe. This was corrected later. The actual data in the article is as I stated here.)
Bottom Line: SAMe was much better than placebo for this difficult patient population. The SAMe product tested at MGH was from NatureMade, a prominent brand of natural products. My personal clinical perspective:
Case reports indicate that SAMe can trigger a manic phase in persons vulnerable to bipolar disorder, as can most other anti-depressants. SAMe can cause transient initial anxiety, nausea, diarrhea as can SSRI’s. But SAMe does not cause sexual dysfunction. There have been no reports of adverse interactions with SSRI’s or reports of hyperserotonin syndrome. Increased homocysteine usually does not occur—a theoretical possibility as Methionine is the precursor of homocysteine.
I recommend starting CFS-ME patients at the lowest available dose, 200 mg, to minimize side-effects. As you know CFS-ME patients tend to be very sensitive to side effects. Increase the dose in increments of 200 or 400 mg as tolerated (usually every 4 to 8 days). Very often we see improvement after 3 or 4 weeks on 800 mg daily or 400 mg bid. However, others require 800 mg bid, as was used at Mass. General.
Please note: SAMe is one of the body’s main methyl group donors. SAMe helps the elongation of carbon chains as in the synthesis of serotonin, norepinephrine, dopamine and other compounds. Folic acid, vitamin B12 and B6 are required. (I usually add a B-complex supplement). Because SAMe plays a key role at many points of metabolism body’s it would not be surprising if SAMe might be helpful in other conditions . For example, there is substantial evidence suggesting benefit from SAMe for osteoarthritis.
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IMPORTANCE: SAMe appears to be an effective anti-depressant. So far it seems to be safe to interact with standard anti-depressant medicines. It causes fewer sexual side effects than SSRI’s. SAMe should be considered along with SSRI’s and Wellbutrin as a main choice for people with depression.
Papakostas et. Al, S-Adenosyl Methionine(SAMe) Augmentation of Serotonin Reuptake Inhibitors for Antidepressant Nonresponders With Major depressive Disorder: A Double-Blind, Randomized Clinical Trial, Am J Psych 2010;167:942-948.
Correction of Error, Fleisch, S, Travis, M, Ryan, N, Discrepancy in Response and Remission Rates for SAMe treated Patients in a Double-blind Randomized Clinical Trial, Am J Psychiatry 167:12, December 2010.
Papakostas, G, Reply to Fleisch et al. Letter, Am J Psychiatry 167:12, December 2010.
Maitake Mushroom: Another Natural Immune System Booster
AHCC, derived from Shitake Mushroom, is high in an immune stimulant compound called alpha glucan. Maitake mushroom is high in a differenct immune stimulant called Beta-Glucan. Drs. Vervicka and Vetvickova at the University of Louisville, Kentucky measured immune system function on mice who had been fed one of five treatments: 1) a placebo compound 2) a well-characterized Maitake Mushroom extract called MaitakeGold 404 purchased from Tradeworks Group, Brattleboro Vermont), 3) an Alpha glucan rich Shitake mushroom purchased from Gourmet Mushrooms, Inc (Sebastopol, CA) 4) a mixture of Maitake and Shitake mushroom, and 5) AHCC purchased from Amino-UP Chemical Company in Sapporo Japan.
After 14 days of oral feeding Natural Killer cell Toxicity was most statistically significantly improved among the mice fed a combination of MaitakeGold (beta glucan) together with Shitake (alpha glucan). MaitakeGold by itself significantly stimulated NK cell functional activity; but MaitakeGold plus Shiitake was even more effective. Shitake alone and AHCC alone were less effective. Phagocytic ability of monocytes and neutrophils were also most improved by the combination of MaitakeGold and Shitake.
IMPORTANCE: If we were to take this research report at face value, our best hypothesis for improving immune function among patients with ME/CFS might be to add either MaitakeGold 404 alone or a mixture of MaitakeGold 404 and Shitake mushroom. These could be given independently or along with antiviral drugs. Not surprisingly, The Tradeworks Group—the U.S. Distibutor for MaitakeGold 404 has also formulated a MaitakeGold/Shitake Mushroom mixture called ImmuNutrin. Operating under the name Nutragensis, the Tradeworks Group sells its products through reputable nutritional companies including Natural Factors, Blue Bonnet and Country Life. My plan is to learn more about human dosing, and pricing directly from The Tradeworks Group/Nutragenesis. Telephone 802-257-2440. Email: firstname.lastname@example.org.
I would appreciate hearing from patients or physicians who gain experience using any mushroom related immune stimulants. As well funded double blind clinical studies are not likely, anecdotal reports from patients and physicians could prove to be valuable.
The Key article: Vervicka, V and Vetvickova J, Immune-enhancing effects of Maitake (Grifoia frondosa) and Shitake (Lentinula edodes) extracts, Annals of Translational Medicine 2014;2(2):14. Article: www.ncbi.nlm.nih.gov/pmc/articles/PMC4202470/.