There is old research that reported that melatonin prevented the androgen receptor [AR] from making its way to the nucleus of the cell. Further, that if the AR was already there, melatonin would kick it out.
If the AR can't get to the nucleus, it can't perform its transcription magic. I took comfort that with 50 mg of melatonin before bed, my cancer might be sleeping while I slept.
From the new (cell study) paper:
"The treatment of melatonin cripples the transcriptional activity of AR, which is essential for the growth of the androgen-dependent prostate cancer cell, LNCaP."
"Cripples"? I never thought I'd see that in a PCa study. Perhaps the meaning was lost in translation, but I like it.
"Melatonin decreases androgen-sensitive prostate cancer growth by suppressing SENP1 expression"
Not earth-shattering news, perhaps, but I'm always happy to see a new melatonin study.
Background: Melatonin is a hormone naturally produced by the pineal gland in the brain. In addition to modulating circadian rhythms, it has pleiotropic biological effects including antioxidant, immunomodulatory, and anti-cancer effects. Herein, we report that melatonin has the ability to decrease the growth and metastasis of androgen-dependent prostate cancer.
Methods: To evaluate the anti-cancer effect of melatonin on androgen-sensitive prostate cancer in vitro or in vivo, the effects of cell proliferation, apoptosis, migration and invasion were analyzed by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry, Transwell assay, and immunohistochemistry (IHC), respectively. Next, the interaction between androgen receptor (AR) and SUMO specific protease 1 (SENP1) was detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting, and confirmed by luciferase reporter assay. Furthermore, the Small Ubiquitin-like Modifier (SUMO) proteins are a group of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. (SUMOylation) of histone deacetylases 1 (HDAC1) was measured by proximity ligation assay (PLA).
Results: The treatment of melatonin cripples the transcriptional activity of AR, which is essential for the growth of the androgen-dependent prostate cancer cell, LNCaP. The lower activity of AR was dependent on melatonin induced SUMOylation of HDAC1, which has been established as a key factor for the transcriptional activity of AR. Mechanistically, the effect of melatonin on AR was due to the decreased SENP1 protein level and the subsequent increased HDAC1 SUMOylation level. The overexpression of SENP1 abrogated the anti-cancer ability of melatonin on LNCaP cells.
Conclusions: These findings indicate that melatonin is a suppressor of androgen-dependent prostate cancer tumorigenesis.
I had been taking 3mg at night. After the discussion on here recently and watching the Shallenburg video I decided to up my dose to 9mg for a few nights until my bottle of 60 mg capsules arrived about a week ago.
The first night on 60 mg I had a vivid dream. Next 6 nights no memorable dreams. Two nights ago I upped dose to 120 mg., dreams came back! ( I hardly ever have dreams that I remember, been that way for many years.)
Unfortunately the side effect seems to be diarrhea. Will cut back to 60 mg. and maybe ramp up more gradually.
Hey scout . I take 20mg but add a 4.5 naltrexone and I have magical vivid dreams 7 yrs . I’m following a Nat onco md . A compound pharmacy gives it to me . Personally , I think 60 or 120 is too much . Try 40! Keep dancing! 🕺💃🏻
The government has run a number of clinical trials on melatonin. Seems like for cancer it might make a slight difference. For sleep it apparently makes a small but measurable difference (I don't recall the number of studies but it was a fair amount and, for the most part, they concurred).
An interesting thing about sleep. I always thought 8+ hours was ideal. I started looking into it, and as you would expect, there are boatloads of research articles and retrospective studies. Sleep vs. cancer and all-cause mortality and cardiovascular issue incidence. I grabbed one chart.
Lots of potential confounding variables but however you slice it optimum sleep doesn't seem to be as critical as exercise/strength.
Some studies:
Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy - PubMed
A Study of the Efficacy of Prolonged-Release Melatonin Versus Placebo in Diabetic Patients Suffering From Insomnia - Study Results - ClinicalTrials.gov
Sci-Hub | Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review. Expert Opinion on Therapeutic Targets, 17(12), 1483–1496 | 10.1517/14728222.2013.834890
Thanks. Respectfully I think that title should belong to Joshua or Nal. I just like to hit the mouse button and bookmark links
I did, however, work out an antioxidant/pro-oxidant threshold for melatonin. If you are the average-sized man then it is about 6 mg. Above that is pro-oxidant and below that is antioxidant. If you have cancer you might want to be at a pro-ox level. If you are trying to support the body and prevent future cancers, antiox.
To be safe I figure >= 20 mg is pro-ox. <= 2 mg is antiox. For a supplement, melatonin has some of the best research and trials backing it. I haven't seen any sides (grogginess, gut disturbances, etc) so take 20+ mg a few nights a week. I haven't pinned down any sleep aid/disturbance in me with melatonin usage. Some research shows that it might help for jet lag to reset your diurnal rhythm and there are a few guys who are "responders". That might be why trials show a small sleep benefit (average gets skewed by a few guys). Over the last few years, I've messed around with 0.1-200 mg without noticing anything. Next month I plan to ask my MO if there she thinks that there might be anything to melatonin.
Have any long-term uses of 20 mg or more of melatonin noticed it harder to fall asleep when occasionally not using it? Any signs that pineal production of melatonin is reduced by supplementing?
I thought I had seen a study strongly indicating there was no effect of prolonged use of melatonin supplementation on the pineal´gland´s melatonin production, but if there is one I can´t find it. All I can find is along the lines of
“A few studies have investigated the safety of melatonin, but none have revealed any serious side effects. It also doesn’t seem to cause any dependence or withdrawal symptoms (5, 6).
Nonetheless, some medical practitioners are concerned that it may reduce the natural production of melatonin in the body, but short-term studies suggest no such effects (7, 8, 9)”. Those studies could not be accessed, and anyway they are short-term.
Thanks for this. I follow the old ways :)I usually sleep 1.5 or 3 hours. Wake up for a couple of hours and then go back to sleep for 3-6 hours. And I usually take a siesta during the day for 45 minutes.
It is hard to pin down the effects of melatonin supplementation on cancer. Still, isn´t the statement that the clinical trials show a slight difference for cancer conservative? In particular, I think about the following studies, which I probably got from your links:
1 Onco Targets Ther. 2018; 11: 7895–7908.
Published online 2018 Nov 8. doi: 10.2147/OTT.S174100
PMCID: PMC6231436
PMID: 30510430
Therapeutic strategies of melatonin in cancer patients: a systematic review and meta-analysis
"Further in our meta-analysis, we collected 20 RCTs about the efficacy of MLT (melatonin) in tumor therapy and summarized the data. ....... The interventions were MLT combined with chemotherapy or other treatments as experimental group and chemotherapy or other treatments as control group. Among them, the dosage and the way of taking MLT are mostly 20 mg/day and taken orally and taken at night, respectively. ...... Through the combination of the results of the study, it was demonstrated that MLT significantly decreased the tumor remission rate compared to the control group (RR =2.25; 95% CI, 1.86–2.71; P<0.00001)............Compared with the control group, the survival rate of cancer patients in the MLT group was greatly improved (RR =2.07; 95% CI, 1.55–2.76; P<0.00001). .......
Based on the above meta-analysis results, it was concluded that MLT, as an adjuvant for the treatment of tumors, can effectively improve the remission rate and overall survival rate of tumor patients", ....................Followed by caveats: . "However, most of the included studies were concentrated in 1994–2002 and the latest research date was 2014. In recent years, most of the subjects involved with anticancer effect of MLT were preclinical studies rather than clinical studies. And, 16 of the 20 clinical studies were completed at the same research center, which suggested certain publication bias evident. It was highly recommend that large-scale RCTs about therapeutic effects of MLT in tumors were conducted in multiple clinical research centers for further study".
Melatonin increases overall survival of prostate cancer patients with poor prognosis after combined hormone radiation treatment
"In the group of patients with poor prognosis, we see the opposite picture. Multi-sided statistical analysis demonstrated a clear positive effect of melatonin administration on long-term survival rates. At a 5-year median follow-up, patients who received melatonin had an overall survival rate that, on average, was 13 months longer as compared to the control group. This conclusion was proven by a multi-factor analysis, where treatment with melatonin served as an independent predictive factor and reduced the risk of death in patients with PCa by more than 2 times"
3
Int J Mol Sci. 2017 Apr; 18(4): 843.
Published online 2017 Apr 17. doi: 10.3390/ijms18040843
PMCID: PMC5412427
PMID: 28420185
Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis In section 3.12 is data from melatonin and prostate cancer mainly preclincal data but a little clinical too.
A possible caveat: lead author is melatonin guru Russell Reiter.
I tend to be on the conservative side. When I see a large-scale non-finance interested RCT I'll be a little more liberal. Until then, it ranks #5 on my supplement list (most supplements are not so great wrt actual data). So I take some.
This is of course my opinion only. Some are going to be even more stringent and others more liberal with their interpretations.
I do exercise daily, too (running, weight lifting), my diet is fully plant based whole wheat, unprocessed, no sugar, no oil, no alcohol. But nuts & seeds. I have statin pills and metformin at home but didn’t start by now as I‘m still on radio therapy (5 more to go) and I should start Erleada. Don’t want to start all at once. Regarding statins and metformin I‘m insecure as I for purpose running on low weight (BMI 19) and don’t know if this wouldn’t be too much. What are your experiences?
Lovastatin doesn't seem to give me many sides. I tried Atorvastatin, Rosuvastatin, and Simvastatin. Atorva and Rosuva gave me horrible insomnia (a rare side effect). Didn't matter what time of day I took them and I reduced the standard starting dose by 50% and then cut it in half again and then went every other day.
Lovastatin works well for me.
Metformin is more problematic. Can give some gastro issues.
Statins and metformin might be particularly good for radiation. My MO agreed with the benefits but I don't know if I asked her about radiation with statins/metformin.
There is some research concluding that statins/metformin/melatonin/curcumin are radiosensitizers/normal cell protectors and I am going to use them when doing radiotherapy (I'll talk to my MO first though).
Sounds like your exercise is great and so is your diet! You might want to consider adding some nuts/olives (I prefer whole organic vs. oil). And some whey protein. Protein is important. There is some observational and Petri dish research that shows it might be best to minimize it. But I asked myself: is it simply that protein is reduced when our way over caloric diets are reduced and simply reflecting that obesity/metabolic syndrome is bad for PCa? Exercise and muscle mass has been more defined to prevent progression. Protein is very necessary for muscle mass. I used to keep my protein low. I finally increased it and started putting on some lean mass. Either way probably doesn't make a tremendous difference though.
10. Differential effects of casein versus whey on fasting plasma levels of insulin, IGF-1 and IGF-1/IGFBP-3: results from a randomized 7-day supplementation study in prepubertal boys – PubMed pubmed.ncbi.nlm.nih.gov/194...
12. Investigation and comparison of the anti-tumor activities of lactoferrin, α-lactalbumin, and β-lactoglobulin in A549, HT29, HepG2, and MDA231-LM2 tumor models – ScienceDirect sciencedirect.com/science/a...
I think anything over 10 mg should give you the pro-oxidant benefits. For sleep, I would think 1 mg would be sufficient (most people aren't helped by melatonin and I never noticed a glaring difference but there might be a few hyper-responders).
Also, I think that because cancer adapts to things, if melatonin is indeed effective then it might be better to take it for a week or two and then stop for a week or so. Just guessing. No studies about this that I recall.
Maybe my 40 mg. dose helps to hold back androgen dependent portion of my aPca, but my newer mets which are CRPC seem to be able to grow fast enough....
I want to draw attention to one of the studies RSH1 cited. The title is Melatonin increases overall survival of prostate cancer patients with poor prognosis after combined hormone radiation treatment It is a retrospective study of PCa patients and reports: " In a multivariate analysis, melatonin administration proved to be an independent prognostic factor and reduced the risk of death of PCa patients by more than twice"
I think it might be a weak aid. Lots of studies and trials but I would expect that given the popularity of the stuff.
I plan to ask my MO about it. What I see now is that there appears to be decent RCT evidence that it very slightly increases sleep duration/quality and shaves a few minutes off of latency. My MO has earned my trust so if she explains why it might be helpful I will take her opinion. If she says there is no possibility that it helps cancer therapeutics I'll reluctantly accept that. In the meantime, it costs me very little and I have never noticed any sides so I plan to take it until she says otherwise.
I am going to ask her a dozen or so questions and will post. Do you recall seeing a post from me about the questions I asked last visit (I don't remember if I posted here or on facebook or both)?
Notes:
02/2022 Summary of notes from MO:
1. Will T stay low more than 1 month on Firmagon?
a. If you're doing Firmagon, you don't necessarily need monthly injections AS LONG AS YOU MONITOR your testosterone to see when it is castrate and when another shot is needed.
2. 5ARIs with Zytiga?
a. Don’t know
3. The half-life of prednisone is 6 hours or less. Is it beneficial to split the 10 mg – or does it matter?
a. Yes, split
4. Do statins reduce adrenal testosterone? Anything else (e.g. aspirin)?
a. Yes, also metformin reduces mTOR.
5. Is it beneficial to suppress FSH? (Relugolix decreases FSH)
a. Maybe, maybe not. Not conclusive.
6. Opinion of SARMs with ADT?
a. Probably fine based on your results of muscle mass increases without affecting PSA
a. Yes, Zytiga, ADT, statins, perhaps metformin, almost certainly fasting.
She doesn't tell people to start using statins or metformin but if they are using them she doesn't tell them to stop unless they are having bad side effects.
I was shocked. She's SOC but reads research and studies and keeps an open mind. I expected her to laugh when I asked about some of this stuff. She brought up metformin and fasting before I even got to the questions.
And both my MO and my urologist agree that we do not have a handle on testosterone. ADT is beneficial but so is high testosterone for other reasons. Off the record, I asked her about Nandrolone phenylpropionate (NPP) and I almost fainted when she expressed support for what I have been doing. As far as I know, it's the only legal AAS. I shoot up a couple of hundred mg at the start of each BAT cycle. It has a short half-life so leaves my system quickly. If I could love a drug I'd love NPP.
I inject 200 mg or 2 cc (100 mg/ml for the stuff I have). Intramuscular injection so really doesn't hurt. I draw with an 18 gauge needle and inject with a 25.
I am playing around with plant brassinosteroids to see if they work. Not androgenic but it doesn't seem to me that they do anything to humans. Still, worth testing out.
I just found out today that your body makes a minute amount of nandrolone. So, sort of natural but natural in much lower doses than what I do on the high phase of BAT.
“It all works, but nothing works well”. My quote, but hopefully we will find a perfect combo of these helpful supplements and drugs that puts this PCa to sleep for 20 years or more!Mike
I've been taking melatonin for years, but will up my nightly dose from 24mg to 60mg and see the results.Vitamatic Melatonin 60mg Fast Dissolve Tablets - 60 Vegan Natural Berry Flavor Tablets - Non-Habit Forming, Sleep Support - Promotes Natural Sleep - Non-GMO, Gluten Free Supplement amazon.com/dp/B09NPMT6N9/re...
Melatonin is illegal in Ireland, when I could import it, it did aid getting to sleep. Now I’m counting sheep, but they keep moving around; very annoying!
That's interesting that it's illegal there. I wonder why? There have been a couple studies about Montmorency Tart Cherry Juice Extracts/Concentrates helping to raise melatonin levels/improving sleep quality. The extract/concentrates do contain a small amount of melatonin, but seem to act on other pathways as well. I am not sure of the quality of the studies, but it might be another option to consider in lieu of supplemental melatonin if you're looking for something to try to improve your sleep.
Best wishes to you in your health journey!!!! And a hat tip to Ireland - I'm about 3/4ths Irish
"OTC melatonin has been banned for years in the United Kingdom (UK), European Union, Japan, Australia and most recently Canada. Exogenous melatonin is not outlawed by these countries but regarded as a medicine, available only by prescription. In the UK and Australia melatonin is approved for the short-term treatment of primary insomnia in adults older than 55 y. In the UK, melatonin with prescription is approved for treatment of some sleep disorders in children with neurological disorders; doses of 2 to 10 mg are permitted but require review for continued use every 6 mo."
Thank you Patrick for all the information you've provided on this and a number of other topics. Your contribution always interesting and informative.
BTW...2mg Melatonin is now available in Australia over the counter...no script needed. 5 mg tablets have just, very recently, become available but only with a prescription. However, as 30 tabs cost about $A250 it's less expensive to buy the 2 mg OTC and just take 2 or 3.
From what I've read, in this thread and other postings on the topic, some men seem to take large amounts. Assuming that they are the same type (modified release) and there doesn't seem to be many complaints about the cost... perhaps they are less expensive in the US than here in Oz. About $A35 for 30 2 mg tabs.
In Ireland, Melatonin is classified as a medicine and because not enough independent testing has been done on it to satisfy the Irish Medicines Boards - the statutory independent body which licenses such things - it has not been authorised for sale here.
Patrick, I have been taking prescription sleeping pills for over 30 years, and recently started taking 10 mg melatonin tablets which haven't reduced my need for drugs. I read that 5 mg was an adequate dosage?
More isn't better when preparing for sleep. One should first try the lowest dose available. 5 mg is much too high.
{"Research has found that taking melatonin in low doses is the most effective way to promote sleep if you are experiencing restlessness or insomnia. Recommended doses of melatonin are from 0.5 mg up to 3 mg, which are adequate to promote sleep or treat jet lag." [1]}
For PCa, though, 10 mg is a cautious dose. For many years, Life extension was alone in offering a 10 mg dose, but they were advising men with PCa to take 40 mg (18 years ago). They upped that to 50mg over a dozen years ago. I'm staying with that dose for the duration.
I just checked with Swanson & there are a score of 10 mg products. When did 10mg go mainstream?
BTW noted in Costco's monthly magazine in the travel section: "According to Travel Medium.com, Bangkok is the most popular tourist destination in the world."
I live about an hour south of Bangkok on the Gulf of Siam. I moved here 17 years ago and have no desire to ever go back to The US. My estranged wife cleaned me out when I left; however, I was fortunate enough to buy my condo while I still had some money. I couldn't afford to live in anything close to it in America since the property taxes alone would exceed my SS entitlement. Fortunately we have no property taxes here, and the COL is nothing compared to The US...can still find delicious dinners for $3.
I'm not aware of anything that will stop ADT resistance (apart maybe from a form of BAT). Resistance to ADT is an almost inevitable consequence of ADT. It does not happen in the absence of ADT. It is an inherent weakness in androgen receptor axis monotherapy.
Thanks so much for telling me about potential effect of melatonin. I will give it a try. I am also seriously considering prostatectomy. I was just diagnosed and the Ca is still within the capsule and has not spread to any organ. I believe I will bit this thing. Again my eternal thanks!
I have never taken Melatonin....... because if you break up the word in Greek it means "members stimulant" and that hits it right on the nose............... All I do is build an imaginary log cabin and I never get past the foundation or the first floor (mind over matter).....To each his own........
There is an unexpected, perhaps, connection between melatonin & melanin.
Wiki: "Melanin (/ˈmɛlənɪn/ ..; from Greek: μέλας, romanized: melas, lit. 'black, dark') is a broad term for a group of natural pigments found in most organisms. ...The melanin pigments are produced in a specialized group of cells known as melanocytes. Functionally, melanin serves as protection against UV radiation."
Lerner [1960) [1]:
"Melatonin is a substance that can lighten the color of frog melanocytes by causing aggregation of melanin granules about the nuclei of the cells"
"The physiological role of melatonin in animals is not known
is it possible that the action caused by Melatonin - in A sensitive PC (not on ADT) cause CRPC -- since it interferes with the AR causing the cancer to find a work around
Will high-dose melatonin by itself induce AR-axis mutations? If there is selection for adaptations, I suspect that the AR would remain very much in play. So no CRPC.
When we attack the AR-axis Putin-style, however, we will ultimately select for cells that do not have AR & have retreated into a stem cell-like form.
With the perfect AR-axis mouse-trap, patients will have an extended time before resistance. But, as Dr. Myers has said, no form of cancer has ever been controled or cured by monotherapy (& if we are on multiple drugs that only target AR, that is still monotherapy IMO. It seems to me that Big-Pharma should be thinking of one or two add-on non-AR-axis drugs that could be combined with Abi or Enza, to double or triple the time to resistance.
My thinking is that (1) a complete cure is still a long way away. but (2) if we can keep the doubling time down to 18 months or two years we could all likely out live it. -- (3) and that the combination of immuno - therapy and less aggressive ADT (so as to not trigger CRPC) is the best way to go until a real breakthrough occurs. Trying to get a zero PSA may be counter productive.
Here are some links which indicate 5-10 mg to be the safe range.
Going over 10 mg. ,IMO, be best left to studies and to be done under close medical supervision. Its a hormone and overdosing it has the risk of unintended results.
I didn´t see any sharp warning against higher doses in these articles. More sort of general unease because we may not know the effects.In the first article, 3 mg was recommended for low-grade PC and 20 mg for advanced PC.
There will be different views, but at this point I would never go below 20mg or above 50mg. I have been on 40mg or 50mg for 18 years & have never suffered from disturbe sleep or daytim sleepiness (I am usually awake & alert at 5 am.)
Would you apply the same dosage recommendation regardless of prognostic indicators and current cancer stage? For example, the study that was referenced in the thread released in 2020 titled "Melatonin increases overall survival of prostate cancer patients with poor prognosis after combined hormone radiation treatment" PMC7566809 used only a 3 mg dosage. Are you inferring a larger dosage could have been significantly more effective?
What I'm really asking is, in your opinion, would you still recommend minimum 20mg for a PCa patient that was intermittent risk with stable PSA < 0.05 2 years post primary treatment in order to reduce the possibility of relapse or could that high of a dose be counterproductive for a patient in that situation?
I have been treating this disease for over 4 years. In the beginning I used melatonin along with other supplements. I was beginning to feel groggy in the mornings and I stopped taking the melatonin. (I have also stopped and started other supplements in my journey). The last couple of years I have had trouble sleeping though out the night, due to having to pee and being awoke by hot flashes.Recently I have added back the melatonin 10mg before going to sleep. I have noticed a huge improvement in my sleeping. I am sleeping though out the night and not having a problem getting back to sleep when having to get up to pee or after a hot flash. I buy 5mg melatonin at Costco here in Canada.
I would like to thank you for all your posts. Like many other posts on this site, I find them very useful and encouraging.I only wish I found this site back in 2017 when first diagnosed.
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