As mentioned above, one of the main endogenous opioids with increased production following low dose naltrexone is met-enkephalin (also known as methionine enkephalin, and as opioid growth factor). A Chinese study published online in August 2016 examined the effects of met-enkephalin on microglial cells in culture [46]. As explained in this study and elsewhere, microglia (the resident macrophages of the nervous system) and macrophages infiltrating from the systemic circulation are actively recruited into tumors, polarized to a tumor-promoting M2 phenotype and away from a tumor-fighting M1 phenotype, and can make up as much as 30% of a GBM tumor. The investigators found that at the optimal concentration of met-enkephalin (1 picomolar), M1-type cytokine production and surface proteins were increased in the microglia, including interleukin-12, TNF-alpha, CD86, CD40, and iNOS. In contrast, M2 cytokines and markers were not affected, including interleukin-10, TGF-beta, CD163, and arginase. Phagocytosis (a main function of M1 macrophages) and cytotoxicity towards U87 glioblastoma cells was increased by met-enkephalin treatment. Thus, met-enkephalin (opioid growth factor), an endogenous opioid whose production is increased in humans following transient opioid receptor blockade by low dose naltrexone, may aid glioma patients by reverting tumor-associated microglia to an M1 anti-tumor phenotype.
View common questions and answers about the use of low dose naltrexone at LDN Science. Especially interesting areinterviews with Dr. Ian Zagon, who discovered the clinical benefits of naltrexone in very low doses.
The effective dose of low dose naltrexone ranges from 2.5 – 10 mg, with the most common dose being 4.5 mg daily. LDN may be taken in the morning or evening. Some individuals may experience sleep disturbances (such as nightmares) caused by LDN and these people may choose to take their daily dose in the morning.
Interesting.
ReplyDeleteI saw it can be bought https://www.ldnscience.org/patients/where-to-buy-ldn but it's a bit sketchy...it says from Israel pharmacy but it is shipped from Singapore. Also you can't pay to them directly but they send you invoice from their "sister company" BotanicLab.
Anyone else is using LDN and has another source of buying it is 4,5mg pills? If I understood correctly you can obtain it via prescription but in 50mg tablets or more?
Naltrexone is an approved drug for opiate and alcohol dependency and does come in 50 mg tablets. The purpose is to continuously block opioid receptors.
DeleteLow dose naltrexone on the other hand is meant to temporarily block opioid receptors for a short time. Naltrexone is not officially approved for this use so does not come in the low dose tablets. This is probably the reason you'd have to source it from foreign countries with different regulations. I can imagine that trying to divide a 50 mg naltrexone tablet into 10 or more pieces might get messy and inaccurate.
If you get a prescription for LDN, a compounding pharmacy should be able to get the right dose for you.
DeleteIf you don't have access to a compounding pharmacy, you could make up a solution using a 50mg tablet. Crush and dissolve in 50ml of vodka, and the solution will have a concentration of 1mg/ml.
DeleteNaltrexone HCL has a solubility of about 100 mg/ml in water, so full dissolution should not be a problem.
Use vodka as a preservative solution, so it will be shelf-stable.
Any undissolved powder in the bottom would be fillers and binders only, and can be ignored.
Use a syringe to dose the solution precisely.
Are you sure about vodka? I asked my friend with pharmacology education how I should prepare the solution and he said in distilled water. And that shelf life is somewhere around 20 days.
DeleteWell, the dose of alcohol one would consume from a teaspoon is pretty trivial. Alcohol-containing elixirs were a vehicle for medications for probably a couple of centuries.
DeleteShe might be right about the 20 days, but distilled water has nothing to impede bacterial growth. Pills often contain starches, which are food for bacteria.
Different chemical suppliers will quote different solubilities, but sellekchem has the solubility of naltrexone hydrochloride as 14 mg/mL in water, and less than 1 mg/mL in ethanol. So there's the possibility that it wouldn't dissolve at 1 mg/mL in ethanol, but this could be tested with a small batch experimentally.
DeleteGood point. The solubility of naltrexone hydrochloride in water will vary by pH of the solution used (becoming a free base in alkaline solution). So there are unknowns with this approach.
DeletePossibly the most sure-fire way of getting a 1mg/ml solution would be to use bacteriostatic water, readily available online. USP-grade bacteriostatic water has a pH of 5.7, which should be just about perfect for this use. Keep in the fridge after preparation, and that should be safe for the 11 days @ 4.5 ml/day. Zero waste and excellent precision.
Stephen do you maybe have access to this article:
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pubmed/27279602
It states: "Continuous treatment with LDN had little effect on growth in different cell lines; however, altering the treatment schedule to include a phase of culture in the absence of drug following an initial round of LDN treatment, resulted in enhanced cell killing."
I guess this drug isn't appropriate for long term maintenance...any thoughts ?
This study seems to miss the point of how LDN is said to work. Taking LDN transiently blocks opioid receptors in the body. The body responds to this by overproducing endogenous opioids, mainly met-enkephalin. None of this would be replicated in vitro. You're better off doing in vitro experiments with met-enkephalin (opioid growth factor) as the discoverers of low dose naltrexone therapy have done.
Deletehttp://www.ncbi.nlm.nih.gov/pubmed/23918871
Thanks!
DeleteAnother thing - I saw that LDN is used in treating multiple sclerosis, with some good results. Since MS is autoimmune disease, one would expect that LDN is inhibiting immune system in CNS?
"Opioid growth factor and low-dose naltrexone impair central nervous system infiltration by CD4 + T lymphocytes in established experimental autoimmune encephalomyelitis, a model of multiple sclerosis: http://www.ncbi.nlm.nih.gov/pubmed/26202376
Great question Matjaz!
ReplyDeleteLDN does seem to be one of a number of agents that can have opposite effects on immune activity depending on the context. I commented briefly about this on Astrocytoma Options in the vitamin D section on the "Re-educating the Immune System" page.
Vitamin D and curcumin are good examples (others might be melatonin and zinc). These agents are shown to have immune-stimulating activity in cancer models, but in the context of an overactive immune response (auto-immune disorders) they dampen down the immune response. A term that has been applied to melatonin is "immune buffer".
Since the immune system is suppressed when there is an actively growing tumor, these agents likely aid in restoring a more functional immune response. A question that has occurred to me that I've not seen studied yet in the lab or clinic is this: would these "immune buffering" agents enhance or limit the effects of a cancer vaccine?
Great question regarding the immune system buffering having enhancing or limiting effects with a cancer vaccine. I used curcumin, vitamin d and melatonin during Dendredic Cell PP65 vaccine. I'm rooting for enhancing effect, but will report in results. I would hope that this type of information which is collected by the center running the trial, could be included in trial stats. This said, I understand the numbers likely will not be there for users (vit. D, melatonin, curcumin) to be scientifically valid either way. Would still be interesting and helpful though.
DeleteWe talked that people also take it in the morning to prevent sleeping problems.
ReplyDelete"The mechanisms involved in the apparent beneficial effect of LDN on cancer have three main elements. The first is the effect of LDN, when taken late at night, in inducing a sharp increase in pituitary and adrenal production of beta-endorphin and metenkephalin, respectively, in the pre-dawn hours, when 90% of the day's manufacture of these hormones occurs. Most studies have shown that naltrexone induces a two to three-fold increase in production of metenkephalin, the endorphin that most specifically activates delta-opioid receptors, the primary endorphin-related anti-growth factor on cancer cells. The low dose of naltrexone, which in higher doses would block endorphin and enkephalin action on the receptor, is gone from the body in about three or four hours — whereas the elevated levels of endorphins and enkephalins persist all day."
From http://www.lowdosenaltrexone.org/ldn_and_cancer.htm
So maybe it would still be a good idea to take it before sleep. I read that some melatonin helps with the sleep disturbances if they occur
I'll share my experience incase it's helpful. I was having horrible nightmares when I started with 4.5 mg/night, so I went to a compound pharmacy. They were able to provide 1.5 mg pills. I dropped down to 1.5 mg for a month, now I'm at 3 mg/night and still no sleep disturbances. Perhaps next month I'll be able to do 4.5 mg, but if not, I'll maintain a 3 mg/night dose.
ReplyDeleteI didn't receive LDN yet but I was thinking of maybe starting with 4,5mg dose in the morning and then going to before sleep dose. And thanks for sharing Jessica :)
ReplyDeleteAnother fresh study :)
ReplyDeleteMethionine enkephalin (MENK) mounts antitumor effect via regulating dendritic cells (DCs):
https://www.ncbi.nlm.nih.gov/pubmed/28088065
Thanks Matjaz - a great study find. Fascinating/very interesting.
DeleteNow I'm thinking about adding a low dose of Naltrexone and collecting all the information.
ReplyDeleteAre the findings of the Naltriben study relevant to Naltrexon?
I can not quite understand the conclusions of this study on the effect of Naltriben.
2017 http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=14496&path[]=46254
In the current study, we report that naltriben:
1) potentiates endogenous TRPM7 channel activity and induces Ca2+ influx in the widely used U87 human glioblastoma (GBM) cell line;
2) enhances U87 migration and invasion;
3) upregulates the MAPK/ERK signaling pathway.
Previously, we reported that the TRPM7 mRNA and protein, as well as channel activity are upregulated in the U87 cells compared to normal human astrocytes [4]. In the current study, we found that naltriben further augmented the TRPM7-like currents in U87 cells. The robust TRPM7 potentiation was stable until washout of naltriben, which was consistent with what other groups reported for TRPM7 overexpressed HEK293 cells or primary ventricular myocytes [14, 16]. For GBM, this is suggestive that although there is already an upregulation of basal TRPM7 activity compared to normal astrocytes, the channel can be further stimulated. The broader implication is that endogenous physiological or pathophysiological signaling pathways in GBM that positively modulate TRPM7 would enhance cancer migration and invasion. Ultimately, this would have devastating outcomes for the prognosis of patients with GBM.
Not really. Naltrexone is a mu-opioid receptor antagonist with very little to no activity at the delta-opioid receptors. Naltriben is specific to the delta receptors.
DeleteSecondly this study was using concentrations of naltriben in the 25-100 micromolar range. Whereas it can inhibit delta-opioid receptors in the subnanomoalr range. I'd be willing to wager that 25 micromolar of naltriben is very far from being achievable in vivo.
Naltriben also doesn't appear to be clinically available, with 0 trials listed at clinicaltrials.gov
NFAT-1 hyper-activation by methionine enkephalin (MENK) significantly induces cell apoptosis of rats C6 glioma in vivo and in vitro.
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pubmed/29324390