Thursday, 2 August 2018

Turmeric/Curcumin – clinically effective in humans after all? SLC6A15 Amino Acid Transporter

Turmeric powder, only in food, modified the SLC6A15 gene

I know that most readers of this blog want to treat autism with supplements and/or diet.
Many supplements and herbal medicines do show promise in the laboratory, when tests are conducted in vitro, but very often when tests are made in humans the results are much weaker, or just not present.  Turmeric/Curcumin is a perfect example; in the test tube it has a wide range of potent benefits, but due to low absorption into humans (bioavailability) it does not show such conclusive results in human studies.
One researcher a while back did send me a study that reviewed all the turmeric/curcumin trials and it concluded that curcumin has no beneficial effect in humans.
In modern medicine anecdotal evidence does not count. Some anecdotes are genuine, but some are coincidence and some are placebo. 

Mini trial of Turmeric at three UK Universities
There is a remarkably good medical program produced by the BBC in the UK, called Trust me I’m a Doctor, where the doctor presenters team up with universities to test practical medical hypotheses.
In one study they took 100 people to assess whether turmeric has any measurable medical benefit. They teamed up with Newcastle University, Leeds University and a clever genetic researcher at University College London (UCL).

They showed that eating turmeric in your food modified a specific gene (SLC6A15) associated with certain cancers, asthma/eczema and depression.
Taking turmeric as a supplement pill or taking a placebo pill had no effect on the gene.
The researcher at UCL was measuring the epigenetic tags attached to the genes. He showed that methylation of this gene was increased by dietary turmeric. Changing the methylation of this gene will change when it turns on/off.
Anecdotally, we know that people who eat a lot of turmeric tend to have less cancer, less asthma and less eczema.
Given that this gene is also associated with depression, you might expect big eaters of turmeric to have either less, or more, depression. Probably nobody has researched this.  

SLC6 Gene Family
It is true that asthma and eczema (atopic dermatitis) are common in people with autism, but variations in the broader SLC6 family of genes are known to affect people with ADHD, Fragile X, Tourette’s and broad autism.
SLC transporters encompass approximately 350 transporters organized into 55 families. The SLC6 family is among the largest SLC families, containing 20 genes that encode a group of highly similar transporter proteins. These proteins perform transport of amino acids and amino acid derivatives into cells. 

In humans, the SLC6 family of transporters defines one of the most clinically relevant protein groups with links to orthostatic intolerance, attention deficit hyperactivity disorder (ADHD), addiction, osmotic imbalance, X-linked mental retardation , Hartnup disorder, hyperekplexia, Tourette syndrome, schizophrenia, Parkinson disease (PD), autism  and mood disorders such as depression, anxiety, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).
This review will focus on the structure-function aspects of the mammalian SLC6 transporters, their regulation by both classical as well as emerging epigenetic/transgenerational mechanisms and what impact these properties may have on disease and the use of biomarkers to detect these proteins in disease states  

The functional impact of SLC6 transporter genetic variation.

Solute carrier 6 (SLC6) is a gene family of ion-coupled plasma membrane cotransporters, including transporters of neurotransmitters, amino acids, and osmolytes that mediate the movement of their substrates into cells to facilitate or regulate synaptic transmission, neurotransmitter recycling, metabolic function, and fluid homeostasis. Polymorphisms in transporter genes may influence expression and activity of transporters and contribute to behavior, traits, and disease. Determining the relationship between the monoamine transporters and complex psychiatric disorders has been a particular challenge that is being met by evolving approaches. Elucidating the functional consequences of and interactions among polymorphic sites is advancing our understanding of this relationship. Examining the influence of environmental influences, especially early-life events, has helped bridge the gap between genotype and phenotype. Refining phenotypes, through assessment of endophenotypes, specific behavioral tasks, medication response, and brain network properties has also improved detection of the impact of genetic variation on complex behavior and disease. 

Amino acids are very important and it is not just that you need them, but you need them in the right place at the right time.
It appears that one of the many effects of defective amino acid/derivative transport into cells is on behaviour.
Improving amino acid transmission is therefore a potential therapy to correct aberrant behaviour, including depression but likely much more. 

Modern clinical trials are often hugely expensive, but as the BBC keeps showing with its TV series, you can carry out very meaningful research without breaking the bank.
You would think that cancer researchers would now look at the modified versions of turmeric that claim higher bioavailability and see if these pills can also modify this cancer gene, since they can easily repeat the UCL laboratory analysis. I doubt this will happen any time soon.
It has long been known that turmeric is not well absorbed, but just one teaspoon a day added to food was enough to modify the gene.
Indians have a low incidence of cancer and a high consumption of turmeric. Turmeric should particularly limit breast cancer.


The above chart, where blue is best, shows India does well, as do some other turmeric eating countries (South Asia and the Middle East). Clearly longevity and quality of healthcare also matter, so beware Africa. Europe, Russia, Argentina, Uraguay, Oz, NZ and North American might want to up their turmeric intake.

We can say that turmeric is a potential epigenetic therapy for at least one important gene (SLC6A15) and possibly more, because turmeric does not just affect methylation. It has several other better documented epigenetic properties. 

Epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression without any change in the DNA sequence, constitutes an important mechanism by which dietary components can selectively activate or inactivate gene expression. Curcumin (diferuloylmethane), a component of the golden spice Curcuma longa, commonly known as turmeric, has recently been determined to induce epigenetic changes. This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment.
Only a few reports have so far investigated the effect of curcumin on DNA methylation. Molecular docking of the interaction between curcumin and DNMT1 suggested that curcumin covalently blocks the catalytic thiolate of DNMT1 to exert its inhibitory effect on DNA methylation. However, a more recent study showed no curcumin-dependent demethylation, which suggested that curcumin has little or no pharmacologically relevant activity as a DNMT inhibitor. To clarify these contradictions, more research is urgently needed.
Given that 5-azacitidine and decitabine, two FDA-approved hypomethylating agents for treating myelodysplastic syndrome, have a demonstrated ability to sensitize cancer cells to chemotherapeutic agents, it would be worthwhile to explore whether the hypomethylation effect of curcumin can also induce cancer cell chemosensitization. Interestingly, a phase 1 trial with curcumin administered several days before docetaxel in patients with metastatic breast cancer resulted in 5 partial remissions and stable disease in 3 of 8 patients. This unexpected high response might have resulted from the clever sequential delivery of these two agents, which capitalized on and maximized curcumin’s epigenetic activity for cancer treatment.

Docetaxel is a 20 year old chemotherapy drug produced using extracts from the leaves of the European yew tree, perhaps best taken with root (rhizome) of the Asian Curcuma Longa plant. 
The main mode of therapeutic action of docetaxel is the suppression of microtubule dynamic assembly and disassembly. It exhibits cytotoxic activity on breast, colorectal, lung, ovarian, gastric, renal and prostate cancer cells.


  1. While I agree that tumeric/curcumin holds potential one also has to keep in mind it quite potently inhibits cyp3a4 and possibly other liver enzymes, this is asking for interactions with meds.

    I feel as if icariin is underresearched, it has potent effects on the brain and have found like bad effects in papers on it, Icariin is very promising imo and its metabolites that are created in the gut.

  2. Turmeric has many other bioactive compounds being actively studied. I even posted about one of them on this blog several years ago:

  3. Okay, I don't understand why taking an extract of a high quality supplement (say gaia, etc) would not be similar in terms of like in food? Seems like the bioavailabilty would be similar? It seems that should be apples to apples (whereas in vivo studies seems to be different). is that clear? MH

    1. MH, this question was posed to the scientists in the BBC program, who replied that using turmeric in cooking, where it is heated and mixed with fats, likely improves how it is absorbed. This is not surprising; supplements are not the same as food.

      Consider potassium supplements vs eating bananas; the amount of potassium taken as a supplement that would kill you, would not harm you if taken in the form of bananas. They are not absorbed at the same speed.

      It would be nice to know how the expensive curcumin supplements compare to dietary turmeric; in terms of what reaches your blood. How many pills from the $30-$50 supplement jar = 1 teaspoon of cheap turmeric taken in food; maybe it is one, maybe it is 10, maybe more.

      I did buy one jar of $50 curcumin and I thought it had a minor effect on allergy, but much less than my $3 pack of antihistamines.

      There clearly are interesting metabolites of curcumin, as Tyler has reminded us; these need to be identified and a potent tablet form created. In the meantime learning to cook with turmeric looks a good idea.

      Unfortunately we cannot rely on supplement companies, lab tests frequently show they do not contain what it says on the label and sometimes the cheapest one is shown far more potent that an expensive one. This is why we have drugs, that are subject to rigorous quality testing; even then, cheap imported generics are sometimes shown not to be comparable to the branded version.

    2. Peter, thanks for clarifying. Your comments make a lot of sense. One additional question -- as you said, there is a range of quality in the supplements so I always wonder in the studies if there would be some difference in the supplement company they choose. But perhaps that is wishful thinking. I would be one of those consumers who would pay extra for a handful of supplements that were rigorously tested. MH

  4. Here is an Alzheimer's study that suggests pH imbalances might be a primary cause of amyloid buildup in the brain:

    Press Release:


    Now, before grabbing for the baking soda, this research suggests that endosomal acidity (i.e. inside the cell) in astrocytes impairs their ability to cleanup amyloid beta.

    The reason I am posting this is that amyloid beta buildup has been linked in cadaver studies of autism patients in what would be considered middle age for most people (40's, 50's), and that HDAC inhibitors have been an active topic of discussion on this blog and HDAC inhibitors were used to fix faulty pH levels in astrocytes which had the effect of restoring their amyloid beta clearance function. Whether there is any direct correlation to autism is an open question, but nevertheless this research might be of use in the future, especially to older people with autism who may have dysregulated astrocytes which may promote early-onset neurogdegeneration.

  5. News on the ERbeta track for remyelination:

    "Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination."


  6. This review article proposes a synergy of BHB and butyrate, and is very easy to read:

    It also mentions BHB dosages used in children (under medical supervision), Alzheimers, Parkinson, microbiome and much more discussed here.


    1. Ling, I do wonder why more use is not made of butyrate in human health, given its extensive use in animal health.

      People taking ketone supplements sometimes add butter to their coffee, to increase their fat intake. Perhaps they should leave the butter out of the fridge and let it get a bit rancid, this produces butyric acid and gives the specific smell. This is much cheaper than buying sodium butyrate capsules.

  7. Hello, Peter. The subject of my comment doesn't belong to this post, but I didn't know where to place it, so I put it here, on the most recent post.
    I've searched the name Thrane on your blog, and it wasn't any result.
    The subject is about Bumetanide in autism treatment, not as a way of reducing chloride, but as a NCKK1 inhibitor to reduce AMMONIA's effect on GABA inhibitory function. This is very different from Ben Ari's conclusion (although the final treatment is the same).
    Here is the study:!po=10.9375

    I really would appreciate your comments about it, Peter.
    Thank you so much.


    1. Very interesting post Luis, thanks for that.
      I seem to respond to supplements that lowers ammonia (citrulline and ornithine) and my urea levels are always elevated. If you the paper you posted is true then I wonder if a simple bloodtest such as elevated urea levels (just under twice the tollerable upper limit myself) is a good indicator of responsiveness to bumetanide.

      Side effect of bumetanide is also elevated urea levels by the way, I wonder if this is simply due to bumetanide helping speed up removal of excess ammonia?

    2. Luis, I am glad you raised the issue of ammonia.
      Many things affect the chloride transporters through which Cl- enters and exits neurons. The transporters are NKCC1 and KCC2 and the K stands for potassium.

      The study shows that ammonia increases the level of potassium outside cells and that this increase over-activates NKCC2 that then lets too much chloride into neurons.
      So one of the reasons that high ammonia is bad for you, is that it increases chloride within cells. If you have autism and already have high chloride this would be bad news.

      Lowering ammonia has been suggested by at least one parent as a strategy to make bumetanide more effective in autism. If you actually have elevated ammonia this would make perfect sense, but if ammonia is at a normal level I doubt there would be a benefit.

      NKCC1 and KCC2 expression is very much affected by inflammation, so many kinds of inflammation and indeed allergy may increase chloride levels and make bumetanide less effective.

      If you respond to bumetanide you want to make sure you limit anything that increases expression of NKCC1 or activates it. You also want to increase expression of KCC2 and try and activate it. This all helps to lower chloride levels within the cell.

      This is all because bumetanide is not very potent at blocking NKCC1, but it is the best drug currently widely available.

      If you have elevated ammonia in your brain you should be taking bumetanide, while also trying to treat the underlying cause.

    3. Oddly though, there a some responders to BCAA (which elevates ammonia). I wonder if the effect BCAA on those who get benefits out of it is mainly due its effect on lowering neurotransmitters such as serotonin and I guess it overpowers the effect it has on ammonia? What are your thoughts on this Peter, I know there are several other readers who their kids respond to BCAA's.

      Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder

      "We recently identified mutations in the gene branched chain keto-acid dehydrogenase kinase (BCKDK) in several patients with ASD, ID and epilepsy (Novarino et al., 2012). BCKDK is the enzyme responsible for the rate-limiting step in the catabolic pathway of the Branched Chain Amino Acids (BCAAs), a group of essential amino acids comprising valine, leucine and isoleucine. The most direct consequence of BCKDK mutations is a hyper-catabolism of the BCAAs, resulting in abnormally low levels of serum and brain BCAAs (Novarino et al., 2012)."

      "Here we studied a mouse model in which Slc7a5 was deleted from the BBB and found that Slc7a5 is particularly important to set brain BCAA levels within a normal range. Mice with defective BCAA transport at the BBB show abnormal activation of the amino acid response (AAR) pathway and a corresponding reduction in mRNA translation along with neuronal activity imbalance and behavioral problems. To probe whether SLC7A5 is essential also in humans, we performed genetic analysis of a cohort of neurological pediatric patients. We identified and functionally validated, mutations in SLC7A5 in several patients with ASD and motor coordination problems. Notably, neurological abnormalities can be treated in adult mice by 3-week long intracerebroventricular (i.c.v.) BCAA delivery."

      Body fluid levels of neuroactive amino acids in autism spectrum disorders: a review of the literature

      Table of the study showing the results of various studies on amino acids measurements:

      Once again, the BCAA's (leucine, isoleucine and valine obviously) consistently show DECREASED, in ALL of the studies, where the other amino acids show inconsistent results, mixed decreased/increased that is.

      So in the first study they talk about BCKDK mutations, which would basically lead to increased breakdown of BCAA's, thus representing a permanent catabolic state. BCAA's

      Branched-chain amino acids and ammonia metabolism in liver disease: therapeutic implications.

      "BCAA supplementation may lead to enhanced ammonia production from GLN breakdown in the intestine and the kidneys and thus exert harmful effects on the development of hepatic encephalopathy."

      "Therefore, to enhance therapeutic effectiveness of the BCAA in patients with liver injury, their detrimental effect on ammonia production, which is negligible in healthy people and/or patients with other disorders, should be avoided. In treatment of hepatic encephalopathy, simultaneous administration of the BCAA (to correct amino acid imbalance and promote ammonia detoxification to GLN) with α-ketoglutarate (to inhibit GLN breakdown to ammonia in enterocytes) and/or phenylbutyrate (to enhance GLN excretion by the kidneys) is suggested. Attention should be given to the type of liver injury, gastrointestinal bleeding, signs of inflammation, and the dose of BCAA."

    4. Effects of oral branched-chain amino acids on hepatic encephalopathy and outcome in patients with liver cirrhosis.

      "Although HE/MHE can be caused by various pathological conditions, including in an accumulation of mercaptans, short-chain fatty acids, and alterations in the gut flora, hyperammonemia has also been implicated in an important pathogenesis of HE/MHE. Besides urea cycle of liver, ammonia can be detoxified in the skeletal muscles by the amidation process for glutamine synthesis using BCAAs. Thus, BCAA supplementation may enhance detoxification of ammonia in skeletal muscle and may be a possible therapeutic strategy for HE/MHE. In this review, we summarize the clinical impacts of BCAA supplementation on HE/MHE and discuss possible mechanisms for a BCAA-induced improvement of HE/MHE."

      All very confusing, the last study states that BCAA's may increase ammonia detoxicification, while other studies show BCAA's increase ammonia.

      Also Peter, as far as I know BCAA raise insulin in muscles atleast I think, not sure if it raises insulin in the brain because that would increase serotonin synthesis through tryptophan hydroxylase activation, while studies obviously show that BCAA's DECREASE brain serotonin and dopamine.

    5. BCAA's compete with aromatic amino acids for entry through the blood brain barrier. Insulin causes muscles to absorb more BCAA's from the blood, thereby allowing more aromatic amino acids into the brain. More phenylalanine and tyrosine means more dopamine and more tryptophan means more serotonin.

  8. Peter and Aspie, I'm not as knowledgeable as you, so here is just my two cents. My son (autistic) has the CBS mutation, that is the cause of high ammonia in all his blood tests. We've tried to control ammonia with ornithine, without any result, so we assume that he probably has the mutation in ornithine decarboxylase enzyme, that blocks ammonia detox through ornithine. Also, his urea is low, wich could be a confirmation of that assumption. The only blood test in which his ammonia level was normal was when he was giving him zeolites. Zeolites do detox ammonia, through adsorption.

    1. Luis, CBS defects are usually an upregulation of the CBS enzyme. This means the enzyme works too fast and this often causes low levels of cystathionine and homocysteine, since there is too rapid conversion to taurine. This leads to high levels of taurine and ammonia.

      BH4 can also become depleted with a CBS upregulation. BH4 helps regulate neurotransmitters and mood.

      CBS mutations can cause intellectual disability and other problems.

      You need to see an expert in inborn errors of the metabolism. Many that lead to intellectual disability and autism are treatable. The treatable ones are on this web site:-

      If you live in the US, go and talk to a specialist at a top hospital like Johns Hopkins, or Boston Children's Hospital.

  9. Maybe add some buttermilk to the curcumin?

    "Buttermilk carries and stabilises curcuminoids. The curcuminoid
    molecules interact with buttermilk components by binding
    to the hydrophobic regions of proteins and partitioning into the
    fat phase. The water solubility of curcuminoids and their stability
    in aqueous media are increased by association with buttermilk. This study suggests that whole buttermilk may be used as a carrier
    for curcuminoids, enabling its incorporation into functional foods."


    1. There is a follow up study using buttermilk yoghurt

      "curcuminoids delivered in yogurt was 15-fold more bioaccessible than curcuminoids in aqueous dispersion"

      "Incorporating of powdered curcuminoids into buttermilk prior to yogurt manufacturing resulted in a 15-fold increase in bioaccessibility of curcuminoids compared to that of neat curcuminoids. Consequently, it is anticipated that similar techniques and approaches could be followed to enrich regular yogurt with curcuminoids, in order to produce healthier yogurt."

    2. They better not sneak curcumin in my yoghurt without my permission, while curcumin has powerfull health benefits its not for everyone.

      Curcumin is a cyp3a4 inhibitor and according to 23andme and im cyp3a4 under/none expressor, so it can even be dangerous for me. I suspect this also one of the reasons I reacted horribly to buspirone, it has powerfull effects on cyp3a4.

      Chlorogenic acid/green coffee extract is a cyp3a4 INDUCER and I respond very well to this. Interestingly progesterone is a PXR agonist and induces cyp3a4. I wonder if I should get my progesterone tested, my testosterone and all that is fine.

      Theres evidence that progesterone controls 5ht2a expression in the cortex! This is exactly where the root of social problems of Aspergers come from (measure by in vivo PET study).

      Medial prefrontal cortex 5-HT(2A) density is correlated with amygdala reactivity, response habituation, and functional coupling.

      Ovarian hormone effects on 5-hydroxytryptamine(2A) and 5-hydroxytryptamine(2C) receptor mRNA expression in the ventral hippocampus and frontal cortex of female rats.

      Now I notice when I drink damiana tea it induces a serene like calm which makes me open to people (damiana has PR binding properties in the brain).

      Estrogen and progestin bioactivity of foods, herbs, and spices.

      Pro-sexual effects of Turnera diffusa Wild (Turneraceae) in male rats involves the nitric oxide pathway

      "So, from our present data, it would appear that the
      plant extracts used in this study, which selectively improve the sexual behavior of sluggish/impotent rats, while being ine¤ective in potent rats, might act mainly by increasing central noradrenergic and dopaminergic tone, and possibly (indirectly) oxytocinergic transmission"

      Also Peter this plant is a rich source acacetin (you mentioned this in an older post), induces il-10, powerfully lowers il-6 to near normal concentrations in the gut of sick rats. On top of that it has mixed anti-estrogenic (through aromatase inhibition) and pro-estrogenic compounds.

      Also vitex agnus castus made me the most emotional I have ever been and it is well known to stimulate progesteron, unfortunately it made me extremely lonely and jealous in the past so I quit it.

    3. Also took a microdose psilocybin 3 days ago, think we have a winner. Annihilates my anhedonia, makes me social (especially on the day that I dosed), but even today I made 2 new friends!

      How come you never talk about the potential of psychedelics Peter for the social aspects of autism.

    4. Aspie1983, LSD was covered 5 years ago in this post:-

      Some people with Asperger's do report positive effects and that some effects can become permanent. This is the problem; you may have a negative effect that becomes permanent.

      For more severe autism, I do not see any point since the social aspects are not the most troubling.

    5. I have a hunch that curcumin is not the only substance where uptake is benefitting from concomitant intake of buttermilk.
      Also resveratrol is indicated ( and maybe also genistein, folate and others (just looking at PubMed titles, I haven't gone deep on the subject).

    6. Ling, it looks like you can use Greek-type yoghurt and I found that in Canada this is a commercial product, not just with curcumin added.
      I know one person using yoghurt as a "carrier" for his teaspoon a day of cinnamon.
      Curcumin is cheap and cost of a teaspoonful is almost nothing. Added to Greek Yoghurt it tastes OK - I tried. It should be good for people with pre-diabetes and they can measure its effect (of lack of), this curcumin/yoghurt combo was effective in diabetic mice.

      High flavanol cocoa would also be good with yogurt. You could also add some butyric acid (leave butter out of the fridge) and make a very functional food therapy.

      Piperine (black pepper) also boosts bioavailability of curcumin. I don't know how that would taste if you added that to the mix!

      I have started to add curcumin to Monty's breakfast yoghurt. 200g of curcumin only cost about 1 euro.

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