Tuesday, 30 July 2019

Ginseng Compound K Esters for some Epilepsy, Autism and Cancers?

Many natural products like Ginseng and Curcumin do have long known medicinal properties but suffer from extremely low bioavailability, which limits their benefit.
Ginsenosides are compounds found in the Ginseng plant. They are metabolized by the gut flora into active compounds that include Compound K.  Compound K has been shown to have a variety of pharmacological actions such as anti-inflammatory, anti-oxidant, anti-cancer and vasorelaxation.  It also has interesting effects that relate to autism and other neurological disorders.

Compound K (CK) has extremely low bioavailability (circa 5%) which limits it potential therapeutic benefit. There are expensive versions of ginseng that aim to maximize Compound K (CK) production in the gut, but they do nothing to improve how much gets from the gut into the bloodstream.

It is possible to modify Compound K by making an ester. This ester has been shown to be highly bioavailable and that means the theoretic benefits, shown in test tubes, might actually be genuinely achieved in humans.

Two types of ester have been studied, the butyl and octyl ester resulting in so-called CK-B and CK-O.

There currently is a $400 million business selling ginseng worldwide, the research and production is mainly coming from Korea and China.  There probably should be pharmaceutical production of CK-B and/or CK-O, but I would not hold your breath.

CK-O was recently proposed as a treatment for some cancers, so perhaps someone will commercialize it.

Interestingly, the standard form CK has been proposed to treat colon cancer, which does make sense since CK is produced in the gut making colon cancer a good choice. You would think that CK-O would work better.

Bcl-2 / Bax

The gene/protein Bcl-2 is relevant to both cancer and autism and has been covered previously in this blog.

A total of 25 genes make up the Bcl-2 family of proteins. Bcl-2 itself is anti-apoptotic while family member Bax is pro-apoptotic.

Apoptosis is programmed cell death.  The Bax/Bcl-2 ratio determines the apoptotic potential of a cell. Increasing the Bax/Bcl-2 ratio can be highly desirable if you have cancer, since what you want is cell death.

Bcl-2 is dysregulated in autism. Studies have shown that the expression of Bcl-2 is significantly decreased in the brain of autistic subjects. This means a reduction in a protein that blocks apoptotic cell death, i.e. this favours growth and too much growth is a bad thing.

The big head type of autism (macrocephaly) is associated with hyperactive pro-growth signalling pathways, so reduced expression of Bcl-2 is not a surprise.

CK-O for some cancer

The Compound K ester CK-O  exerts strong anti-tumour activity by suppression of anti-apoptotic protein Bcl-2 and increase of pro-apoptotic protein Bax. It increases the Bax/Bcl-2 ratio.

CK-O from some epilepsy and some autism?

There are many types of epilepsy and hundreds of types of autism.
One commonly shared feature is the imbalance between the GABA-mediated inhibition and the glutamate-mediated excitation.

CK-O looks likes it might help both conditions.

·        CK is shown to reduce the expression of NMDA receptors and to attenuate the function of the NMDA receptors in the brain.

·        GABAB receptor activation via CK can regulate KCC2 at the cell surface in a manner that reduces intracellular chloride and hence the reversal potential for GABAA receptors

·        The expression of KCC2 protein was elevated by the treatment of CK while the expression of NKCC1 protein was reversely down-regulated.

·        CK enhances the expression of GABAA receptor subunit α1 in the brain and exhibits a tendency to decrease the expression of NMDAR1 protein in the hippocampus.

Ginseng for Autism?

There is some weak evidence that Ginseng may help in some autism.

I think what is really happening is that the effect is weak rather than the evidence is weak.  Ginseng may have a weak positive effect in some autism; weak because the amount of Compound K absorbed is trivial.

If Ginseng helps, CK-O could be substantially more effective.

Ginseng,as a GABAb Antagonist, as an "Add-on Therapy" for some Autism? Also Homotaurine and Acamprosate

We demonstrate that GABABR activation can regulate KCC2 at the cell surface in a manner that alters intracellular chloride and the reversal potential for the GABAAR

In the trial below the dose appears very low at 250mg. In the more encouraging study in ADHD the dose was 1000mg twice a day.

Autism is a pervasive developmental disorder, with impairments in reciprocal social interaction and verbal and nonverbal communication. There is often the need of psychopharmacological intervention in addition to psychobehavioral therapies, but benefits are limited by adverse side effects. For that reason, Panax ginseng, which is comparable with Piracetam, a substance effective in the treatment of autism, was investigated for possible improvement of autistic symptoms. There was some improvement, which suggests some benefits of Panax ginseng, at least as an add-on therapy.

I would not expect a dramatic effect from any commercial Ginseng product, but CK-O really could have an effect.

Although there are many research reports regarding the bioactive function of ginsenosides and ginseng, studies on the neuroprotective eect and eects on the cognitive function of compound K are limited. It is generally agreed that compound K is more bioavailable than the parent ginsenosides, including Rb1, Rb2, and Rc, and is the major contributing factor to the health benefits of ginseng. However, as most studies were conducted using disease-associated models, such as Alzheimer’s disease and ischemic stroke, the results cannot be directly translated to the healthy normal population. Furthermore, it is not clear whether compound K can cross the blood–brain barrier and exert any action on cognitive function in humans, even though the compound was reported to facilitate GABA release in the hippocampus and exhibit a protective effect against scopolamine-induced hippocampal damage in a mouse model. The possible mechanisms of action of compound K in neuroprotection and cognitive improvement include attenuation of ROS levels in neural cells through induction of antioxidant enzymes, regulation of NO, GABA, and serotonin receptors, Ca 2+ channel modulation, regulation of the MAPK pathway, and inhibition of inflammation.
Although ginseng and ginsenosides were shown to have neuroprotective and cognitive enhancing eects, further research is required to establish whether compound K is the major component of ginseng responsible for cognitive improvement in humans.

The imbalance between the GABA-mediated inhibition and the glutamate-mediated excitation is the primary pathological mechanism of epilepsy. GABAergic and glutamatergic neurotransmission have become the most important targets for controlling epilepsy. Ginsenoside compound K (GCK) is a main metabolic production of the ginsenoside Rb1, Rb2, and Rc in the intestinal microbiota. Previous studies show that GCK promoted the release of GABA from the hippocampal neurons and enhanced the activity of GABAA receptors. GCK is shown to reduce the expression of NMDAR and to attenuate the function of the NMDA receptors in the brain. The anti-seizure effects of GCK have not been reported so far. Therefore, this study aimed to investigate the effects of GCK on epilepsy and its potential mechanism. The rat model of seizure or status epilepticus (SE) was established with either Pentylenetetrazole or Lithium chloride-pilocarpine. The Racine’s scale was used to evaluate seizure activity. The levels of the amino acid neurotransmitters were detected in the pilocarpine-induced epileptic rats. The expression levels of GABAARα1, NMDAR1, KCC2, and NKCC1 protein in the hippocampus were determined via western blot or immunohistochemistry after SE. We found that GCK had deceased seizure intensity and prolonged the latency of seizures. GCK increased the contents of GABA, while the contents of glutamate remained unchanged. GCK enhanced the expression of GABAARα1 in the brain and exhibited a tendency to decrease the expression of NMDAR1 protein in the hippocampus. The expression of KCC2 protein was elevated by the treatment of GCK after SE, while the expression of NKCC1 protein was reversely down-regulated. These findings suggested that GCK exerted anti-epileptic effects by promoting the hippocampal GABA release and enhancing the GABAAR-mediated inhibitory synaptic transmission.

Absorption mechanismof ginsenoside compound K and its butyl and octyl ester prodrugs in Caco-2cells.


Ginsenoside compound K (CK) is a bioactive compound with poor oral bioavailability due to its high polarity, while its novel ester prodrugs, the butyl and octyl ester (CK-B and CK-O), are more lipophilic than the original drug and have an excellent bioavailability. The aim of this study was to examine the transport mechanisms of CK, CK-B, and CK-O using human Caco-2 cells. Results showed that CK had a low permeability coefficient (8.65 × 10(-7) cm/s) for apical-to-basolated (AP-BL) transport at 10-50 μM, while the transport rate for AP to BL flux of CK-B (2.97 × 10(-6) cm/s) and CK-O (2.84 × 10(-6) cm/s) was significantly greater than that of CK. Furthermore, the major transport mechanism of CK was found as passive transcellular diffusion with active efflux mediated by P-glycoprotein (P-gp). In addition, it was found that CK-B and CK-O were not the substrate of efflux transporter since the selective inhibitors (verapamil and MK-571) of efflux transporter had little effects on the transport of CK-B and CK-O in the Caco-2 cells. These results suggest that improving the lipophilicity of CK by acylation can significantly improve the transport across Caco-2 cells.

Panax ginseng C.A. Meyer, the active components of which are mainly ginsenosides, is frequently utilized as a herbal drug in traditional oriental medicine. These ginsenosides, which belong to the class of triterpene saponins, have been reported to possess various biological and pharmacological activities such as antiaging, antiinflammation and antioxidation in central nerve system, cardiovascular system and immune system. Previous studies have shown that the pharmacological actions of ginsenosides contributed to their metabolites through biotransformation by human intestinal bacteria. Compound K (CK; Figure 1) is one of the main pharmacologically active metabolites of protopanaxadiol ginsenosides (e.g., Rb1, Rb2 and Rc) and it was reported that, it was accumulated in the liver after absorption from the GI tract to the blood, and some CK was transformed into fatty acid esters which may be the active components of ginsenosides in the body. Many studies revealed that most of the ginsenosides are poorly absorbed along the human intestinal tract due to a high polarity. Odani et al. have reported that the amount of ginsenoside Rg1 absorbed via oral administration was within the range of 1.9−20.0% of the dosage in animal models. Other ginsenosides such as Rb1 and Rb2 were also slowly absorbed through digestive tract, and the oral bioavailabilities in rats were relatively low. The biological activities of drugs depend not only on their chemical structures, but also on their degree of lipophilic and membrane permeation, which could enhance their transport across the cell membrane or influence their interaction with proteins and enzymes. Recently, considerable attention has been paid to the development of ester prodrugs, which is a widely used approach to improving overall lipophicity, membrane permehave been reported to enhance its lipophilicity, bioavailability and in vivo activity. However, to date, limited information is available concerning the mechanisms of oral absorption for CK and production of ester prodrugs to enhance the oral absorption of ginsenoside CK. To increase the oral absorption of CK, esterification provides a route to obtain more lipophilic derivatives. In addition, it has been reported that acylation of cholestane glycoside increased the antitumor potency. Several acylated triterpenoid saponins isolated from the roots of Solidago virgaurea subsp. virgaurea in a low concentration also activated the metabolism of endothelial cells, which enhanced the permeability of the blood vessel walls for better adsorption of the saponins into tissues. We thus speculated that the novel ester prodrugs of CK, butyl and octyl esters (CK-B and CK-O; Figure 1), which are more lipophilic than parent compound, may have an excellent oral bioavailability. The objective of this study was to determine the transepithelial transport and absorption mechanisms of CK and its ester derivatives in the Caco-2 system. Caco-2 cell monolayers have been generally accepted as an in vitro model for prediction of drug absorption across human intestine and for mechanistic studies of intestinal drug transport since these cells show morphological and functional similarities to human small intestinal epithelial cells. In this study, both ester derivatives were utilized for transepithelial transport and absorption assays in Caco-2 monolayers compared with CK to investigate whether esterification could enhance the membrane permeability of high hydrophilic compound, thus improving the intestinal absorption of drug.
Our results are consistent with the previous reports which showed that CK had a low oral bioavailability (approximately 5%) in rats. However, as shown in our results, the low oral bioavailability of CK can be improved by esterification of CK into CK-B and CK-O.

Octyl ester ofginsenoside compound K as novel anti‐hepatoma compound: Synthesis and evaluation on murine H22 cells in vitro and in vivo

Ginsenoside compound K (M1) is the active form of major ginsenosides deglycosylated by intestinal bacteria after oral administration. However, M1 was reported to selectively accumulate in liver and transform to fatty acid esters. Ester of M1 was not excreted by bile as M1 was, which means it was accumulated in the liver longer than M1. This study reported a synthetic method of M1‐O, a mono‐octyl ester of M1, and evaluated the anticancer property against murine H22 cell both in vitro and in vivo. As a result, both M1 and M1‐O showed a dose‐dependent manner in cytotoxicity assay in vitro. At lower dose of 12.5 μm, M1‐O showed moderate detoxification. Instead, M1‐O exhibited significantly higher inhibition in H22‐bearing mice than M1. M1‐O induced murine H22 tumor cellular apoptosis in caspase‐dependent pathway given that pan‐caspase inhibitor, Z‐VAD‐FMK, could reverse the cytotoxicity induced by M1‐O. Additionally, pro‐ and anti‐apoptosis proteins, Bcl‐2 and Bax, altered and consequently induced increased expression of cleaved caspase‐3. Interestingly, cyclophosphamide regimen significantly induced atrophy of spleen and thymus, main immune organs, while M1‐O treatment greatly alleviated this atrophy. Collectively, we propose M1‐O as a candidate for live cancer treatment.

M1-O exerted strong anti-tumor activity by suppression of anti-apoptotic protein Bcl-2 and increase of pro-apoptotic protein Bax

Note: M1-O is the same think as CK-O

Ginsenosides are isolated from the Panax quinquefolius. This is a natural product triterpene saponins and steroid glycosides. Ginsenosides are the members of a dammarane family, which consists of a 4-ring and steroid-like structure. All ginsenosides have two or three hydroxyl groups in the carbon 3 and 20. Ginsenosides are converted into active metabolites like 20(S)- protopanaxadiol Rb1-Rb3, Rc, Rd, Rg3, Rh2, Rs1 (2) with help of human gut bacteria -glycosidase Eubacterium sp. A-44. Ginsenosides produced a variety of pharmacological activities such as anti-inflammatory, anti-oxidant, anti-cancer and vasorelaxation.                                                                                                                                                                       

Emerging signals modulating potential of ginseng and its active compounds focusing on neurodegenerative diseases



The ginseng compound K ester CK-O is likely to be a potent drug in humans with a range of effects, some of which do relate to autism and epilepsy.

Very often people with epilepsy are excluded from autism clinical trials.  Here is one drug where you might want to start with that very group.

CK-O will have multiple effects, meaning it is not selective, so while it may have some very good effects, there may be some negative ones.

You might think the CK-O molecule would be a good basis on which to build a modern patentable drug; a K-O (knock-out) for someone.

Natural substances with health benefits like phytoestrogens (soy etc), curcumin/turmeric, ginseng and even bee propolis either need to be eaten in large quantities or the active substance identified and synthesized. The people with neurofibromatosis (NF-1, NF-2) consuming large amounts of expensive New Zealand propolis as a PAK1 inhibitor might as well save money and buy the active ingredient itself another ester, this time caffeic acid phenethyl ester, and gives the bees a rest.


  1. Here is some very interesting and novel research showing that in genetic mutant fruit flies that expressed no microRNA's (which is supposed to lead to death as microRNA's are important gene regulators), slowing metabolism by 50% allowed the fruit flies to grow to normal healthy adults:

    Press Release:


    This is fascinating with respect to autism, because the theory behind this intervention allowing these mutant fruit flies to mature when under a normal dietary regimen they would die, is that by slowing development down, the repair mechanisms in the organism have a chance to correct errant proteins or errors in developmental trajectory due to having more time to do so before cell division. This research is also fascinating because mutant or else dysregulated genes like PTEN which lead to hyperactive mTOR activation, may exacerbate developmental problems because they cause the organism to grow faster than normal, thereby preventing developmental errors from having the time to be corrected as well (just my hypothesis).

    Now, I am not going to go starve my child anytime soon, but it would be very interesting to see what the effects of caloric restriction happen to be in the many mouse models of autism including developmentally induced models such as valproate which do not genetically mutate mice, but instead epigenetically dysregulate mice via HDAC inhibition.

    Of course much of the damage with respect to autism is done in utero, but it still might be possible that if some autisms are diagnosed early enough, slowing the metabolism of a child (i.e. slowing development down), might give them a better chance at a more neurotypical developmental trajectory (this is all my speculation by the way).

    Of course humans are not fruit flies, hence why diving deeper into this idea with mouse models which may reveal themselves over the course of only a year or so of research would be a relatively simple experiment to undertake that should not require a whole lot of technical expertise and financial resources to undertake.

    1. Why not go directly to caloric restriction mimetics for humans?


    2. Most of the mimetics deal with increasing cellular repair and autophagy, whereas what is going on in this study is not just the effects of CR mimetics, but also the fact metabolism is slowed down considerably so that cells during development literally have more time to correct their errors. RNA can only be sequenced so fast in a cell. Large proteins (many of which are mutated in genetically induced autism with de novo mutations affecting single proteins) can take over 24 hours so in that case you are going to want a very slow developmental metabolism.

      Think of it like a construction company with a competent foreman but a bunch of drunk, lazy, and incompetent laborers. The foreman may be able to correct errors as they inevitably happen, but not if the construction job is rushed too fast.

    3. Thank you for Tyler, I enjoyed that very simple scene you used to explain it all. :-)


  2. Peter, can you please expand on the "This means a reduction in a protein that blocks apoptotic cell death, i.e. this favours growth and too much growth is a bad thing".
    Wouldn't more apoptosis favour less growth or am I just tired?
    Anyway, it looks like my daughters mutated gene is a promoter of Bcl-2, so I guess there is too little of it in our home.


    1. Ling, it looks like I was the tired one!

      Apoptosis is good if you want less growth, for example in cancer.

      There is clearly a contradiction in our current understanding as shown in the paper below.

      Statins reduce increase apoptosis via reducing Bcl-2 in cancer cells but have the opposite effect in non cancer cells.

      Statins, Bcl-2 and Apoptosis: Cell Death or Cell Protection?

      So in your case Atorvastatin should have an effect, but will it be positive or negative?

    2. That is a good question Peter, and I haven't got a chance yet to learn the answer.

      As you write, Bcl-2 seems bad in (most) cancer cells:
      "These findings indicate that Bcl-2 inhibits resveratrol-induced apoptosis by a mechanism that interferes with cytochrome c release and activity of caspase-3 that is involved in the execution of apoptosis."


  3. Hello Peter and community,

    Hope everyone is having a great week!

    I just found a very interesting article that could be relevant to our efforts:

    "Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice"

    What is great here is that the researchers tested a number of drugs and natural compounds to see which ones would enhance KCC2 activity, and they have provided the data in the article. While the article focused on Rett Syndrome and Mecp2 mutations, knowing which compounds enhance KCC2 activity would (in my opinion) benefit anyone affected by neuronal chloride imbalances.

    Interestingly, we can also look at the mechanisms of action to find other potential natural compounds that may help.

    I wanted to share as I think this is a very interesting list of compounds (includes Resveratrol, Piperine, Luteolin, etc.).

    Have a great evening everyone!


    1. Very interesting finding AJ!

      The Rett gene MECP2 is dysregulated in many other neurological diseases. I think Peter mentioned REST last year(?):
      "Our results support the notion that SIRT1-mediated reduction in REST expression is a likely link between resveratrol treatment and increased KCC2 expression."


    2. Hi Ling,

      Hope all is well!

      I find papers like this one so useful as they identify many compounds that will work against a specific target, just in case this is relevant to our unique situations. I believe KCC2 will be relevant to many cases above and beyond Rett/Mecp2, and in fact, I wonder if there is any additive / synergistic benefit to those already benefiting from Bumetanide (i.e. both blocking NKCC1 and increasing KCC2 versus just blocking NKCC1).

      With all the research that is going on today, I'm hopeful that we'll all have more options to improve our children in the near future.

      Have a wonderful day Ling!


  4. Hi Peter, and community
    Would c-ko cancel out the anti hypertension effect of l types like verapamil more than regular ginseng? If so that might be beneficial for me because I have pots symptoms, which is probably the only reason I got access to diltiazem and verapamil in the first place. I haven't actually tried a ginseng supplement with my stack/poly pill because I had read a little about the change to adoptosis but didn't completely understand it, at least when I read it. Since finding your blog I usually wait too try things if I feel like it might be something you might post about unless I manage to communicate my idea effectively to my doctors. I think my autism might be from ehlers danlos hypermobility type, I plan on going to the center for genomics in Cambridge ma for testing.

    Oh, what would you recommend for ginseng dosing?


    1. Martin, you cannot buy CK-O, which is a pity. You can try regular ginseng, but I doubt it will have much effect at any commonly used dosage.

    2. Peter, that is too bad. I haven't been able to decide what to do at my next cardiologist appointment. I'm unsure whether I should stay on verapamil because I can't sleep on it but I can if I take diltiazem. I had tried to get Losartan with my verapamil hoping the effect on nitric oxide would let me sleep and have more exercise tolerance, but I always am told no. Do you know any DAN type doctors or psychiatrists in New England?

    3. ^-Martin

      Sorry I have been procrastinating on setting up my profile thing. Thanks

    4. Martin, DAN doctors mainly became MAPS doctors.

      Here is their membership list.

      I think they tend to all have their favorite therapies, rather than being a "one-stop-shop".

    5. Peter, thank you for the link. I had my first appointment with the connective tissue specialist I found in Cambridge, MA this past week and in the letter to my PCP they stated I clearly have a "connective tissue disorder within the Ehlers-Danlos syndrome/Loey-dietz syndrome spectrum." I didn't get a specific sub type diagnosis because I can't afford the genetic testing, but I don't think it's super important right now anyway. They also listed POTs and dysautonomia with night sweats specifically; and that I am observant about my signs and symptoms of my autism and physical problems. The one thing that really did surprise is that I actually have macrocephaly, which they said it's likely familial but still could be part of my autism. I guess my idea of what a big head is was exaggerated because no one told me I have one before.

      I know they aren't on the MAPS list, but I do highly recommend them based on my experience so far.

      Center for Human Genetics, Cambridge, MA


    6. Peter,
      I'm not sure what page of the blog would be the best to ask this but I figured since I already commented today I'd ask here.
      I have been wanting to try fluvoxamine for awhile now but I'm worried about how many other drugs it seems to interact with, (I had the pharmacy I use check it against my current 'poly pill'). I remember seeing that Petra uses it with her son but I think I remember her commenting it can't be used with other drugs/treatments discussed on your blog. If I was going to try it I would cut a 25mg either in half or in quarters, assuming my psychiatrist was on board. I'm interested not just because of the sigma 1 agonism but that it promotes oligodendrogenesis in Ms research I've seen. I still haven't found a place in Massachusetts to fill my clemastine but I've kind of been procrastinating on that, and somehow the Walgreens and cvs I tried used up all my scripts refills even though they never were able to fill it. I have been thinking of trying to call Teva and ask them which suppliers/pharmacies carry their Clemastine in the us.

      Thank you

    7. Martin, the MS research shows that fluvoxamine does have anti-inflammatory and oligodendrogenesis activities, so you would expect some people with autism to benefit.

      All SSRIs can have side effects, which your psychiatrist can advise you about. As for interactions with other drugs you need to ask the doctor and pharmacist.

      Some SSRIs when given at a low dose actually have a negligible effect on serotonin and you just get some of their other effects, or no effect. Low dose Prozac is a good example, mentioned in this blog.

      Let us know if it does indeed give you a benefit.

    8. This comment has been removed by the author.

  5. Hi all, I have ordered bumetanide and can buy it from International Apotheke of Chiasso, Swiss....they said it is called Burinex and the company is Leo....Anyone using this commercial product? I am living in Italy and apparently it is not available in Italy thanks for any help carla marta
    carla marta

    1. Carla Marta, Leo Pharma is based in Denmark and I expect their bumetanide is good quality.

  6. Though resveratrol and PDE4 inhibition have both been covered on this blog before, this new research suggests maybe taking another look at resveratrol would be worth our time:

    Press Release:


    PDE4 is an enzyme that is necessary to yield corticosterone which is excessively elevated in the various autism studies which have looked at the matter. Though there are other PDE4 inhibitors out there such as rolipram, many of them have more side effects than resveratrol which also happens to have other properties useful to autism (mTOR inhibition, etc.). An elevated HPA axis besides causing long-term health problems, also of course causes acute cognitive problems as well so anything to reduce excess corticosterone output is likely to improve overall autism symptoms as a therapy.

    1. Tyler, resveratrol and Pterostilbene are indeed interesting, but are they potent enough in humans?

      It would be great to have some anecdotal evidence comparing Ibudilast vs Resveratrol vs Pterostilbene in people with autism.

  7. Tyler, can you describe what kind of acute cognitive problems?


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