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Monday, 23 May 2016

More Melatonin!




  Older people, those with autism, those with reflux, IBS/IBD and other GI problems generally have low levels of melatonin.  Poor sleep is but one consequence.



I have previously written about the potential for melatonin in autism and I do not just mean to improve sleeping disorders.  Melatonin does a great deal more than that.

Melatonin for Kids with Autism, and indeed their Parents


MitoE, MitoQ and Melatonin as possible therapies for Mitochondrial Dysfunction in Autism. Or Dimebon (Latrepirdine) from Russia?




Most substances I write about in this blog are either prescription drugs or quite expensive supplements.

Other than in a small number of countries like the United Kingdom, melatonin is widely available as a cheap supplement, but that does not mean it is not a drug.

In humans melatonin is produced in two different places and it appears in two orders of magnitude.  Traditionally melatonin is considered to be a hormone produced by the pineal gland in the brain, but far more melatonin is actually produced in your intestines, where it has completely different functions.

Many people have low levels of melatonin, for example people with autism/schizophrenia/bipolar, older people and people with intestinal problems ranging from reflux/GERD/GORD to ulcerative colitis.

We know that melatonin is a potent antioxidant, but there are numerous other antioxidants.  Damaging oxidants vary both by type, but also by their location and so if you are clever you would match your antioxidant(s) very specifically to the oxidant(s).  

So if you have elevated risk of prostate cancer, take lycopene, it accumulates in fatty tissue and the prostate is surrounded by a fatty deposit called periprostatic adipose tissue (PPAT).  It is not agreed whether lycopene can cross the blood brain barrier in humans; it does for sure in rats.  

It seems that in people with type 2 diabetes there is oxidative stress in the mitochondria of the beta cells in their pancreas.  Beta cells make insulin and in type 2 diabetes there is often a gradual loss in beta cells resulting in type 1 diabetes.  Numerous cancer studies have shown the potential of different antioxidants in different cancers, NAC in breast cancer, Sulforaphane is esophageal cancer etc.  It seems to be agreed that antioxidants are most helpful in disease prevention, rather than cure.  
  
We know that melatonin is potent at combatting oxidants in the mitochondria, so logically people with mitochondrial dysfunction might well benefit from melatonin.  It is vastly cheaper than the antioxidant drugs that target the mitochondria (MitoE, MitoQ etc).

An interesting recent study has linked low levels of melatonin in the parents of those with autism.


  
Background: Low melatonin levels are a frequent finding in autism spectrum disorder (ASD) patients. Melatonin is also important for normal neurodevelopment and embryonic growth. As a free radical scavenger and antioxidant melatonin is highly effective in protecting DNA from oxidative damage. Melatonin deficiency, possibly due to low CYP1A2 activity, could be a major factor, and well a common heritable variation. ASD is already present at birth. As the fetus does not produce melatonin, low maternal melatonin levels should be involved. Methods: We measured 6-sulfatoxymelatonin in urine of mothers of a child with ASD that attended our sleep clinic for people with an intellectual disability (ID), and asked for parental coffee consumption habits, as these are known to be related to CYP1A2 activity. Results: 6-Sulfatoxymelatonin levels were significantly lower in mothers than in controls (p = 0.005), as well as evening coffee consumption (p = 0.034). In mothers with a second child with ASD and/or ID, 6-sulfatoxymelatonin levels were lower compared to mothers with one child with ASD (p = 0.084), 

Conclusions: Low parental melatonin levels, likely caused by low CYP1A2 activity, seem to be a major contributor to ASD and possibly ID etiology.


I think you would also find, more generally, high levels of oxidative stress in parents of those with autism, and more importantly oxidative stress during pregnancy would have negative effects.  I think autism produces stress and stress helps produce autism.

  

Potency of pre–post treatment of coenzyme Q10 and melatoninsupplement in ameliorating the impaired fatty acid profile in rodent model ofautism


  

  
"It is now almost 60 years since the discovery of melatonin and new physiological functions of the indole continuously appear in the most recent studies worldwide. Besides the pineal gland, the existence and value of other sources of synthesis force us to rethink the established premises about the biological role of this molecule, such as the well-known regulation of circadian and reproductive cycles (Hardeland et al., 2008). In the last few years, other properties of melatonin such as antioxidant power, immunoregulatory capacity, and oncostatic action have enriched our knowledge about the pleiotropic nature of the hormone.

The role of melatonin in mitochondrial homeostasis has gained strength in the scientific community. Experimental evidence emphasizes its importance as a stabilizer of organular bioenergetics, which could be related to the             prevention of development of aging and several diseases.

  
Role of melatonin on mitochondrial dysfunction and diseases

The idea that mitochondrial dysfunction is implicated in the etiology of various diseases has been strengthened after several years of research. Initially, studies of mitochondrial diseases have focused on mitochondrial respiratory-chain diseases associated with mutations of mtDNA. However, more recent evidence shows that oxidative damage is responsible for the impairment of mitochondrial function, leading to a self-induced vicious cycle that finally culminates in necrosis and apoptosis of cells and organ failure. We are now starting to understand the mechanisms of a large list of mitochondrial-related diseases (cancer, diabetes, obesity, cardiovascular and neurodegenerative diseases, and aging); all of them seem to share the common features of disturbances of mitochondrial Ca2+, ATP, or ROS metabolism (Sheu et al., 2006). Therefore, selective prevention of such phenomena should be an effective therapy in a wide range of human diseases (Smith et al., 1999; Sheu et al., 2006). Melatonin, as was described in the previous section, has many of the characteristics of a perfect candidate for the treatment of these kinds of illnesses.

  
Conclusion

Mitochondrial dyshomeostasis and related events have begun to reveal themselves as possible etiologies of several diseases of unknown origin. In the next years, conscientious investigation about this topic should be undertaken by scientists of different research areas to achieve a better understanding of the molecular mechanisms implied, which will ultimately allow the development and clinical application of efficacious treatments."


Recent posts looked at disturbed calcium homeostasis in autism, particularly low bone density.  Melatonin may play a role here as well.



Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women.


Abstract


The purpose of this double-blind study was to assess the effects of nightly melatonin supplementation on bone health and quality of life in perimenopausal women. A total of 18 women (ages 45-54) were randomized to receive melatonin (3mg, p.o., n=13) or placebo (n=5) nightly for 6months. Bone density was measured by calcaneal ultrasound. Bone turnover marker (osteocalcin, OC for bone formation and NTX for bone resorption) levels were measured bimonthly in serum. Participants completed Menopause-Specific Quality of Life-Intervention (MENQOL) and Pittsburgh Sleep Quality Index (PSQI) questionnaires before and after treatment. Subjects also kept daily diaries recording menstrual cycling, well-being, and sleep patterns. The results from this study showed no significant change (6-month-baseline) in bone density, NTX, or OC between groups; however, the ratio of NTX:OC trended downward over time toward a ratio of 1:1 in the melatonin group. Melatonin had no effect on vasomotor, psychosocial, or sexual MENQOL domain scores; however, it did improve physical domain scores compared to placebo (mean change melatonin: -0.6 versus placebo: 0.1, P<0.05). Menstrual cycling was reduced in women taking melatonin (mean cycles melatonin: 4.3 versus placebo: 6.5, P<0.05), and days between cycles were longer (mean days melatonin: 51.2 versus placebo: 24.1, P<0.05). No differences in duration of menses occurred between groups. The overall PSQI score and average number of hours slept were similar between groups. These findings show that melatonin supplementation was well tolerated, improved physical symptoms associated with perimenopause, and may restore imbalances in bone remodeling to prevent bone loss. Further investigation is warranted.

           Melatonin Effects on Hard Tissues: Bone and Tooth


Melatonin, as an endogenous hormone, participates in many physiological and pharmacological processes. The above analyzed data indicate that melatonin may be involved in the development of the hard tissues bone and teeth. Decreased melatonin levels may be related to bone disease and abnormality. Due to its ability of regulating bone metabolism, enhancing bone formation, promoting osseointegration of dental plant and cell and tissue protection, melatonin may used as a novel mode of therapy for augmenting bone mass in bone diseases characterized by low bone mass and increased fragility, bone defect/fracture repair and dental implant surgery. The investigation of melatonin on tooth still insufficient and requires further research.

The following very interesting study, looking at the broader effects of high dose melatonin in autism, has been completed, but the results have yet to be published

Melatonin Dose-effect Relation in Childhood Autism (MELADOSE)

the objective of this clinical trial is to study the relation between the melatonin dose administered and its effect on severity of autistic impairments especially in verbal communication and play.


Experimental: 2 mg melatonin
1 tablet of 2mg melatonin and 4 tablets of its placebo once a day, an hour before falling asleep, for 6 weeks.
Experimental: 4 mg melatonin
2 tablets of 2mg melatonin and 3 tablets of its placebo once a day, an hour before falling asleep, for 6 weeks.
Experimental: 10 mg melatonin
5 tablets of 2mg melatonin once a day, an hour before falling asleep, for 6 weeks.




The science part

The following is an extract from an excellent paper about the use of melatonin to treat ulcerative colitis:-







Melatonin was first described as a secretion from the pineal gland with multiple neurohormonal functions, including regulation of the circadian rhythm, reproductive physiology, and body temperature, but has since also been found to inhibit the Cox-2 and NF-_B pathways and several aging processes. The multifactorial role of this hormone, however, has only relatively recently been appreciated (Fig. 1) as it circulates unimpeded across anatomical barriers, the blood– brain barrier included, and exhibits both receptor-dependent and receptor-independent effects.

Furthermore, melatonin exhibits a high degree of conservation across the evolutionary ladder, pointing to a critical function in various forms of life, even in organisms devoid of a pineal gland. In fact, the analysis of extrapineal sources of melatonin have highlighted the GI tract as a major source of this factor, with concentrations of melatonin as much as 100 times that found in blood and 400 times that found in the pineal gland.40 GI melatonin comes from both pineal melatonin and de novo synthesis in the GI tract and may have a direct effect on many GI tissues, serving as an endocrine, paracrine, or autocrine hormone, influencing the regeneration and function of epithelium, modulating the immune milieu in the gut, and reducing the tone of GI muscles by targeting smooth muscle cells.40 Melatonin may also influence the GI tract indirectly, through the central nervous system and the mucosa, by a receptor-independent scavenging of free radicals leading to reduction of inflammation, reduction of secretion
of hydrochloric acid, stimulation of the immune system, COX-2 fostering tissue repair and epithelial regeneration, and increasing microcirculation. Human intestinal motility follows a circadian rhythm with reduced nocturnal activity. Abnormalities in colonic motor function in patients with UC have been well documented.

Melatonin appears to be involved in the regulation of GI motility, exerting both excitatory and inhibitory effects on the smooth musculature of the gut.  The precise mechanism through which melatonin regulates GI motility is not clear, although some studies suggest that this may be related to blockade of nicotonic channels by melatonin and/or the interaction between melatonin and Ca2+ activated K channels.

Melatonin may also function as a physiological antagonist of serotonin. In a recent rodent model, melatonin administration was shown to reverse lipopolysaccharide-induced GI motility disturbances through the inhibition of oxidative stress. The net motor regulation by melatonin is, therefore, likely multifactorial.

In addition, several lines of in vitro studies as well as animal studies, have reported that melatonin regulates the extensive gut immune system and has important general antiinflammatory and immunomodulatory effects. Given its
presence in GI tissue and its suggested importance in GI tract physiology, it is reasonable to hypothesize that melatonin could influence inflammation-related GI disorders, including UC. In various animal experiments, melatonin administration was (among other immunomodulatory effects) shown to increase
IL-10 production and inhibit production of IFN-_, TNF-_, IL-6, and NO, suggesting that melatonin may exert benefits in UC by reducing or controlling inflammation.

Melatonin administration has also inhibited the TNF-_-induced mucosal addressin cell adhesion molecule (MAd-CAM)-1 in vitro, and intercellular adhesion molecule (ICAM)-1 in vivo, limiting the influx of activated _4_7_ and LFA-1_ leukocytes to the mucosal environment. During inflammation, the mucosal microvasculature controls the selection and magnitude of influx of T-cell subsets into the gut through cell adhesion molecules expression and chemokine secretion, which further amplify the communication with other leukocytes and cells. In animal experiments neutralization of MAdCAM-1 and ICAM-1 led to attenuation of mucosal damage in colitis.


If you made your way through the above section, and regularly read this blog you will appreciate the multiple possible beneficial actions for many types of autism.

I was going to have a post about GI issues, but I will put some of the melatonin part in this post.  In summary, very many GI problems are associated with low levels and melatonin and numerous studies have shown that giving oral melatonin is an effective treatment to varying degrees. Melatonin is a useful adjunct (add-on) therapy in these conditions. 

Not only does melatonin appears to promote healing of the esophagus but also the tightening of the LES (The lower esophagealsphincter)

Failure of this sphincter to close is why people get reflux/GERD/GORD.

One possibility is that the night time spike in melatonin signals your brain that it is time to sleep and also signals your LES to shut tightly, so that during the night acid does not rise up your esophagus while you are horizontal.



The potential therapeutic effect of melatonin in gastro-esophageal reflux disease


Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and aminoacids: comparison with omeprazole.   




Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases





Conclusion

Melatonin may already be the most widely used drug to treat autism, but generally at the lower sleep-inducing doses.

It would seem that those with GI problems, mitochondrial problems or more general oxidative stress may very well benefit from the higher doses of melatonin already used by some.

Older people, people with esophagitis/duodenitis or IBS/IBD, people with type 1 or 2 diabetes and even people with osteoporosis may also want to look into melatonin supplementation.

Given the supplement is ending up in your intestines, where much melatonin should already be being produced, the impact on pineal melatonin production becomes less of an issue.  People giving thyroid hormones T3 and T4 to children who are euthyroid (ie normal thyroid function) should be aware of the consequences (thyroid shutdown).

For various reasons, production of ROS (reactive oxygen species) that are the oxidants varies throughout the day, the morning is the worst time supposedly.  Ideally you would match this with your antioxidant intake.  One combination would be melatonin before bed, a larger dose of NAC at breakfast and then NAC throughout the day.  As highlighted in an earlier post, sustained release NAC is also interesting, but it would help if there was a more potent version. 

Hopefully Dr Tordjman will publish the results of her high dose melatonin in autism study soon.
  
Most people struggle to access the really effective autism drugs, but antioxidants are available in abundance.

Oxidative stress is not a cause of autism, but it is a common side effect.  Treating oxidative stress does indeed seem to help many people with autism, but since the source of those oxidants may vary so should the most effective therapy.  Melatonin may be a useful part of that antioxidant mix, particularly if there are GI, mitochondrial or sleep issues.

Melatonin has a half-life of less than an hour, people who respond well might consider sustained release versions, which are available quite cheaply (5 and 10 mg sustained release forms look interesting).  There are even some clinical trials measuring the resulting plasma levels.











25 comments:

  1. Is there an explanation why Verapamil depletes our body's melatonin?

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    1. Petra there is an explanation, see below. Verapamil does not affect melatonin secretion, but does affect how the body processes it (renal and/or hepatic handling).

      Plenty of people take both. It could be argued that people on verapamil should take a melatonin supplment.

      http://www.ncbi.nlm.nih.gov/pubmed/9179543

      "For this purpose, eight healthy volunteers were infused with calcium and saline on separate days and in random order (experiment A). Hypercalcaemia inhibited nocturnal melatonin secretion by 20% but left urinary melatonin excretion unaffected. If exogenous hypercalcaemia inhibits melatonin secretion, it is reasonable to assume that calcium channel blockers such as verapamil might have the opposite effect. This was investigated in experiment B, in which eight healthy subjects were treated on separate occasions with oral verapamil and placebo. Verapamil did not affect nocturnal melatonin secretion but increased melatonin excretion by 145%. As 6-sulphatoxy-melatonin is the main melatonin metabolite excreted by the kidneys, it was considered important to find out whether verapamil would also influence the excretion of 6-sulphatoxy-melatonin. This was investigated in experiment C, in which eight healthy volunteers were treated, on separate occasions, with oral verapamil and placebo. In this experiment also, verapamil increased urinary melatonin excretion significantly (by 67%), but left excretion of 6-sulphatoxy-melatonin unaffected. These findings imply that verapamil influences the renal and/or hepatic handling of melatonin."

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  2. Agomelatine,trade name Valdoxan, is a melatonergic antidepressant with a chemical structure very similar to melatonin.
    It caught my attention a year ago, when my son responded well to melatonin. It is approved only for adults and there are case reports of its successful use in refractory OCD. Maybe you can have a look at it?

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    Replies
    1. It is a melatonin receptor agonist, developed to be a more potent version of melatonin. It has a longer half-life, but not by much. Melatonin receptors do many clever things and I supposed if you have oxidative stress you will have a lower level of melatonin, then these receptors are not activated enough.

      Are you using sustained release melatonin? This kind of melatonin should give all the benefits of Valdoxan.

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  3. I read this about a couple weeks ago:

    https://www.sciencedaily.com/releases/2016/05/160512124913.htm

    It discusses one potential side-effect of melatonin supplementation in certain individuals with a mutation in a gene that affects a type of melatonin receptor which causes them to release less insulin with increasing levels of melatonin.

    Full disclaimer: I think melatonin supplementation benefits, even at high doses, outweigh the risks at this time and I supplement it myself. Nevertheless, side effects of any supplement should be considered and dealt with (if possible). Obviously, to make use of this information, one would need a genetic test done, but even then low insulin release can be dealt with through dietary measures by not dumping a lot of fast acting carbohydrates into the body (insulin spikes are not necessarily bad if you are not diabetic but high blood sugar with no way for the body to clear it is pretty much always bad).

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    1. Tyler, good to remind readers that drugs/supplements will inevitably have side effects in some people. People need to be cautious.

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    2. An interesting paper I am sure you will be very interested in came out in the last couple days:

      http://www.cell.com/neuron/fulltext/S0896-6273(16)30158-1

      Basically, what is suggests is that fixing the E/I imbalance in developmental disorders might be trickier than once thought, especially with regards to GABAergic drugs in that while many interneurons may function to dampen excitatory pyramidal cells, other interneurons may function to dampen those same interneurons and so a broad acting GABAergic may end up potentiating interneurons that dampen or silence another group of interneurons, thereby potentially worsening the E/I imbalance. This of course happens in the basal ganglia where you have inhibitory circuits inhibiting other inhibitory circuits that inhibit areas of the cortex, but this paper suggests this may be a broader phenomenon where the proper E/I plasticity is defined by early development sensory stimuli. This study was done on tadpoles, but it likely means the same phenomenon throughout the mammalian brain may be in play here. It could also explain some of the paradoxical effects of GABAergics in autism that go beyond GABAergic plasticity with respect to dysregulated interneuron chloride homeostasis.

      Here is a brief description of the paper:

      http://neurosciencenews.com/experience-brain-development-4320/

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    3. On a more positive note, there is a research group working on schizophrenia that suggests (at least in schizophrenia which is related to classic autism in many ways) the brain is constantly trying to repair itself from the tissue damage resulting from schizophrenia pathology:

      http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=10339175&fulltextType=RA&fileId=S0033291716000994

      This is very encouraging news to us parents who have not just "accepted things as they are" and a good counter to anyone who tells us we should just give up on our kids and move on with our lives because they believe that the brains of those with classic autism are set in stone and that the proper focus with them should be to merely teach our children rudimentary life skills (and nothing more) because they believe it is impossible for them to ever have the intellect to course their own path in life.

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    4. Tyler, it is interesting. The fact that autism is not degenerative and most often mellows after childhood suggest something similar must be happening in autism. It would be useful to understand what changes with age, since it might then be possible to accelerate that self-repair process.

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    5. There are quite a few remyelinating drugs in the pipeline for MS which I believe will be a necessary long-term therapy (among probably many others) to help undo a lot of the damage to the long-range and thick white matter fibers that seems to be compromised in autism. Unfortunately, nobody that I am aware of is seriously even thinking this big with respect to autism because there is no consensus that those with autism (which is a very broad category) need to have their brains repaired, while MS and the dementia diseases are looked at by many researchers as potentially repairable brain disorders. I mean, from my vantage point the research and tools are being built, but that they are not being built for treating autism, nor is anyone even trying to apply that research and those tools to autism which is both hopeful and depressing at the same time.

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    6. Tyler there is an interesting drug called Ibudilast, that one reader uses. It is a Japanese drug for asthma maintenance therapy, so very widely used. It has been licensed to a US company to develop as an MS therapy. It is similar in use to Singulair, but has a different mechanism of action. If you want to try it look online for an English speaking Doctor in Japan. They often dispense their own drugs, so he could prescribe it to you and mail it to you. Since you can make good scientific arguments, you may well find people more willing to help than you expect. Because you do not use a questionable on-line pharmacy, you just pay the regular price and an airmail stamp.

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  4. I ordered TTFD (Alinamin) from an on-line Japanese pharmacy and they also sell Ibudilast OTC. Are you aware of any questionable pharmacies in Japan that should not be used for safety reasons?

    Recently I've found an interesting case report about high dose melatonin use in MS:
    http://www.ncbi.nlm.nih.gov/pubmed/25546814

    It is about a women with the most severe primary progressive form of MS who was poorly responding to typical treatment until she started melatonin 50-300 mg per day which stopped further demyelination and she partially recovered, which as the authors note, is unusal in this form of MS. She used melatonin for 4 years as the only treatment and with no side effects.

    In most animal studies on melatonin they use very high doses.

    After I inreased melatonin for my son from 3 mg to 10 mg according to studies on melatonin for migraines, it was the only situation in his life that he spontaneously asked me for "a pill for head" next day. I did not realize that he was aware of any association between meds and his condition until then.

    I wonder what would be the best melatonin dose?

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    Replies
    1. They are selling prescription drugs without a prescription and so they can charge a lot more, in one case $775 for 28 tablets that should cost $300, which is already vastly expensive.

      I do not think they will sell fakes of cheap drugs and Ibudilast should be cheap.

      Petra was giving 10mg of melatonin.

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    2. Agnieszka, 10mg melatonin seem to support my son against oxidative stress during sleep time and I can see that upon waking.
      I think melatonin helps preventing depressive like symptoms. It doesn't usually help with late onset sleep disorder.
      I ended up with 10mg because Peter told me, according to research for oxidative stress, we need twice as much as the sleeping induce dose. In some trials they even used 20mg.
      I also wonder what the dose would be.

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    3. Thanks Petra,

      Actually I first gave my son 3 mg for jet-lag more than 2 years ago not being aware about melatonin and autism associations then. And even with only 3 mg I noticed behavioral effects and I realized that it cannot be attributed just to an additional hour of sleep he gained. Now I give 15 mg, occasionally even more.

      Off topic, Petra I would like to ask you if I understood your comments correctly: can you buy Verapamil OTC in Greece?

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    4. Hi Agnieszka, I don't think we could name this buying procedure OTC.
      It is like a loosening of the protocole that the law leaves it somehow "open". Things get very strict only if the drug is featured as "recreational" drug. Then you need a "red line" prescription.
      Verapamil is supposed to be prescribed by a doctor each time you buy it, normally, but the pharmacists seem eased to give it.
      I can't explain it further because I am not a lawyer or a pharmacist. It is a matter of "burocracy" which appears everywhere, at least in Greece.
      Please treat this information with respect.

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    5. Hi Petra, thanks for explaining this to me.

      I am also not a lawyer nor a pharmacist. I know people bought Bumetanide without Rx in Southern Europe to bring it to Poland as here this med is not available at all. I personally like when "bureaucracy" is patient friendly, which I can't say about my country, where Rx on-line orders from abroad were banned last year. Anyway thank you!

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    6. Agnieszka, I agree with you. Buying Verapamil without prescription is a patient friendly paradox of the Greek "bureaucracy". The worst face of "bureaucracy" is not being able to get hold of a drug that yoy need to survive.

      Bumetanide is also a drug that by law is supposed to run in pharmacists in Greece, yet it disappeared from the market. Otherwise I would have trialled it by now. I checked in close country Macedonia and they also don't have it. I think you can find it in Bulgaria but I can't be sure. When you say southern Europe which countries do you mean?

      I would also like to ask you if you would need my son's case report before the conference. If you do I will probably not have finished with medical examinations by 18 June, so his medical profile won't be in detail.

      I'll send you an email to verapamil.asd@gmail.com to discuss this further.

      Delete
    7. Petra, do you have Furosemide in Greece? This does exactly the same thing as bumetanide it affects NKCC1/2. It is weaker and so the pills are usually 40mg, whereas bumetanide is 1mg.

      Delete
    8. Hi Peter, I just checked with the pharmacy,and yes, we have it, only in 40mg pills. The stronger versions have also "disappeared".
      Thank you, I didn't know that it's the same.

      Delete
    9. Petra it is just as you wrote that it's about survival for many of our children, maybe it would all be easier when more people understood that.

      I know about Spain where Bumetanide is sold as Fordiuran.
      UK on-line pharmacies used to deliver rx meds abroad provided that EU prescription was sent to them, but I don't know if this is still the case.

      Thank you for your proposal regarding your son's data. I thought I would mostly include information about my son, he has so complex medical issues that it is more than enough for the time frame. But now I think you have a very good idea to include a short summary about other people who reported using Verapamil. If you and your son don't mind this I would be happy to email you about this.

      Delete
    10. Petra, the only question is whether it crosses the blood brain barrier as much as bumetanide. Bumetanide does not cross so well itself. You would need to trial it for at least 2-3 weeks and all the fluid lost via diuresis needs to be replaced. So he should drink an extra liter of water a day and add back potassium (bananas or potassium supplement). Ideally measure blood K+ levels before starting and a week or two after.

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    11. This comment has been removed by the author.

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  5. All the talk of melatonin made me remember this article:

    Adenosine triphosphate inhibits melatonin synthesis in the rat pineal gland.
    http://www.ncbi.nlm.nih.gov/pubmed/26732366

    Standard reserves applied, it seems to link melatonin with Dr. Naviaux work on purines.

    Jane.

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  6. Peter, would long term melatonin use shift immune system to th1 dominance?

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