High Dose Melatonin Therapy

[Agron]

Okay, I have tried CBD and have taken it for a long time but it does not help me sleep. I have even got the CBD with melatonin in it and certain types specifically formulated to help you sleep.

Also, I do have autoimmune issues so perhaps I shouldn't be messing with melatonin at all.

@Mrs. Peel
Maybe Ashwhagandha root tea could be of help. I use it sometimes and it allows for a peacefull sleep. Ashwhagandha is an adaptogen and is calming and soothing. Since it handles stress you can sleep better. Maybe it would help with your autoimmune issues too. Its been used in ayurveda for a loooong time and is seen as very important. Used as a tonic for general health. It has a broad spectrum of action. It certainly did wonders for me so I can only recommend. And Im lucky since it is now grown here in Croatia too.. If you want a recipe just ask.

Heres good info on what it can do :
(western styled review of properties)

Ashwagandha - Nootropics Expert

Ashwagandha is a powerful anti-anxiety and antidepressant nootropic supplement. But should NOT be used if you dealing with kidney or liver disease. Or are hypothyroid.

nootropicsexpert.com

Indian:

Ashwagandha Herb Uses, Benefits, Cures, Side Effects, Nutrients

herbpathy.com

 

[goyacobol]

What kinds Melatonin brand is best and purest? Can anyone like to recommend?

@Kay Kim ,

The brand I am using is Nature Made 5 mg but I don't know if it is the best. Maybe others can recommend other good brands. I just noticed they have 10 mg gummies which might be convenient to take.

 

[Laura]

If you are taking high doses, you want pure melatonin without a lot of excipients.

 

[Mrs. Peel]

Maybe Ashwhagandha root tea could be of help. I use it sometimes and it allows for a peacefull sleep. Ashwhagandha is an adaptogen and is calming and soothing. Since it handles stress you can sleep better. Maybe it would help with your autoimmune issues too. Its been used in ayurveda for a loooong time and is seen as very important. Used as a tonic for general health. It has a broad spectrum of action. It certainly did wonders for me so I can only recommend. And Im lucky since it is now grown here in Croatia too.. If you want a recipe just ask.

Hi Agron,

While I haven't tried the tea, I've been taking Ashwagandha in capsule form for some time now as adrenal support, although frankly I really don't notice any effect.

Thanks anyway.

 

[Agron]

Hi Agron,

While I haven't tried the tea, I've been taking Ashwagandha in capsule form for some time now as adrenal support, although frankly I really don't notice any effect.

Thanks anyway.

I have taken it during the day (powder mixed with water or juice) with an energizing/relaxing effect. Making tea before sleep gives a different, almost sedative effect. 4-5grams in a dose. Tea is 15minute boil on lowest heat.
I always feel ashwagandha root when I take it so maybe you got some that is not good. And I never take it with food. In the evening I dont eat anything at least 4 hours before bedtime.

 

[Ant22]

This thread caught my interest and although my health has gotten much better over the years I'd be interested to try higher doses of melatonin. I have some persistent symptoms that just won't go away for good and I'm open to experimenting to see if something gets rid of them.

I've been taking half a sublingual 5mg pill per night (so roughly 2.5mg) and that pretty much knocks me out within 20 minutes. Holding a conversation becomes a challenge, so does doing anything other than lying down and drifting off. If the recommendation is to start at 10mg at 3pm and build it up to 30mg per day, and then go up to 50mg per dose, then how does one manage to still keep their eyes open to take later doses?

That said, I noticed that if I take too much it makes me extremely drowsy but I struggle to fall and stay asleep. But the most I've ever taken was 6mg, I'm really not sure if 150mg would allow me to stay awake.

If anyone here tries it, I'd be interested to learn how the body responds to such doses. I'm normally at work at 3pm and I don't get home until 6-7pm so the only time I could try this is a holiday - which won't be until Easter. My only option would be starting to take it from 6pm onwards but I still fear I'd just sleep through the time for the next dose.

 

[Laura]

I notice that there are some books about melatonin therapy on amazon. Might be a good idea to read one or two of them and extract some of the basics.

 

[Keit]

It seems to point to evening/night time dosage of melatonin, except in shift workers where the circadian rhythm might need to be manipulated with artificial light/darkness exposure+ melatonin.

A common variant in MTNR1B—MTNR1B rs10830963 is associated with increased risk of type 2 diabetes, increased fasting plasma glucose levels and impaired early insulin secretion (177, 178). Moreover, late dinner, associated with elevated melatonin concentrations (as in night shift workers, above), impaired glucose tolerance in “gain of function” MTNR1B risk allele carriers but not in non-carriers. These data suggest that circulating melatonin is related to the development of Type 2 Diabetes, in a deleterious sense. Of course sleep restriction is also associated with impaired glucose tolerance, increased risk of metabolic syndrome and/or diabetes (179, 180). So that the usefulness of melatonin to address sleep problems may well increase risk of metabolic abnormalities.

This issue of the circadian rhythm and the relationship between melatonin and insuline resistance got me interested after reading in FoundMyFitness report that I have specific variants of MTNRB1 and MTNR1A genes that are rather problematic in this regard. The insulin resistance issue wasn't really surprising, considering that I have diabetes type 1 and 2 in my family on my mother's side. What was really surprising is learning about the role melatonin plays in all this.

I still need to do further research on the topic, but what I was able to gather so far, that it is a very good thing that I stopped doing night shifts. Apparently sleepless nights are more detrimental while having this MTNR1A variant. And I am indeed a very light sleeper, and need to take definite steps toward minimizing exposire to blue light in night time.

Another issue with MTNR1B rs10830963 that, as the above quote indicates, eating (particularly carbs) after sunset is not a good idea. Neither eating early breakfast. And while not eating breakfast was never a problem for me, evening eating is something I often practice. I do practice intermittent fasting, at least twice a week, but right now it usually means that I don't eat until 16 pm and then eat all evening up to a time I need to go to sleep.

It seems that in this case what would be ideal is having an eating window of 11 am - 19 pm with two meals, or a big meal and snacks per day, and the rest is fasting. Well, something to work on! Especially considering the family history.


So I am attaching two screenshots from the report that have the explanation about the gene variants, and also here are two links to FMF clips about it. The first video was actually linked to in the report and starts at the specific point when they talk about melatonin. But the rest of the talk is also interesting.

According to "Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation" (1995), there were no side effects with 300mg of melatonin per day, except that it inhibited ovarian function and can thus be considered along with a progesterone-like molecule for contraception.

That's another issue that I am dealing with and researching right now. Funny how melatonin appears to rule and influence a lot of things in our life!

And while reading about it I found the following report, that appears to be quite comprehensive: "Light Exposure, Melatonin Secretion, and Menstrual Cycle Parameters: An Integrative Review"

 

[Anamarija]

I have downloaded several books about melatonin and there's a tone of information. Since I'm not expert in this field and English is not my native language can somebody help me to point me how to search through all of this. I presume that we looking for right doses to experimenting with melatonin, right?
Here's the books that I have:

The Pineal Organ, Its Hormone Melatonin, and the Photoneuroendocrine System
Melatonin after Four Decades: An Assessment of Its Potential
Tryptophan, Serotonin, and Melatonin
Yolanda E. Soriento - Melatonin, Sleep and Insomnia
Role of Melatonin and Pineal Peptides in Neuroimmunomodulation
Extreme Dose! Melatonin The Miracle Anti-Aging Hormone Anti-Alzheimer’s Hormone Anti-Baldness Hormone Menopause Reversal Hormone
Melatonin: Biological Basis of Its Function in Health and Disease
Ronald Ross Watson - Melatonin in the Promotion of Health
Melatonin: Therapeutic Value and Neuroprotection

 

[Laura]

Ark and I experimented for about a week. We found that taking it AFTER dark was best, so it was 3 doses of 30 mg at 6, 8 and 10, and then bed. It sure did something, but we stopped because it seemed to be affecting our day functioning. Like, I was incredibly sleepy and slow... I'll wait until we have some of the powder to experiment again. Maybe higher doses aren't so tiring?

One thing I CAN say, I now go to sleep MUCH faster and easier and don't have the problem with ruminating at night, and I AM sleeping more than I did before the experiment, which is a blessing.

 

[Andrian]

For about a week I experimented with melatonin by taking 10 -15 mg late in the evening. So, my sleep improved considerably taking in the account the fact that I'm working during the night sometimes (now less than a couple of months ago) I had really a hard time to sleep during the night thus being stressed and feeling like a zombie sometimes. Another thing I've noticed is that finally I can remember my dreams, that's a good thing, I had problems remembering them for a looong time. During the day I'm feeling good, calm, full of energy, more focused at my daily tasks... So yes I agree there is definitely something about melatonin, I'm curious in trying to experiment by taking 20 mg daily for a couple of weeks and see how it will go. I have the "feeling" that the melatonin is the right "antidote" i was looking for for a long time against the "obstructions" in my brain let's say. Will see how it goes.

 

[Konstantin]

I am taking melatonin every day in dose from 1 to 6 mg ( usually 3mg ) for almost 4-5 years.
It helps me sleep better. The highest dose that I have tried was 9 mg. The only effect I noticed from this dose was good night sleep.

On a few occasions, I noticed that when I took the regular dose of melatonin of 3 mg that I can't fall asleep at all. I feel so fresh the whole night. It happens only a few times in all these years that I am taking melatonin.

When that happens I stop taking melatonin for a few days and then I restart taking melatonin again. This insomnia goes the next day when I stop melatonin.

I found one good and long article about melatonin

The Therapeutic Potential of Melatonin: A Review of the Science - PMC

www.ncbi.nlm.nih.gov

and here what is says about mega doses

The acute toxicity of melatonin as seen in both animal and human studies is extremely low. Melatonin may cause minor adverse effects, such as headache, insomnia, rash, upset stomach, and nightmares. In animals, an LD50 (lethal dose for 50% of the subjects) could not be established. Even 800 mg/kg bodyweight (high dose) was not lethal.[138] Studies of human subjects given varying doses of melatonin (1–6.6 g/day) for 30–45 days, and followed with an elaborate battery of biochemical tests to detect potential toxicity, have concluded that, aside from drowsiness, all findings were normal at the end of the test period

Probably timing is also very important

Although melatonin is a potential adjunctive agent in the treatment of cancer and immune deficiency, poorly timed administration can produce opposite effects. Melatonin injections given in the morning stimulate tumor growth,[46,148] whereas the same doses in midafternoon have no effect but in the evening have a retarding effect. And although some people with depression may suffer from a “low melatonin syndrome,”[27] melatonin administration that unduly prolongs the nocturnal melatonin rise, or that is given throughout the day, may exacerbate SAD[82] and bipolar and classic depression.[83] Finally, animal studies have shown that moderately large doses of melatonin (equivalent in one study to about 30 mg in adult humans) increased light-induced damage to retinal photoreceptors

Melatonin has also been suggested for use as a contraceptive for women,[145] which might raise the question of whether melatonin damages the female reproductive system. Notably, no side effects were reported in a report of a phase 2 clinical trial in which 1400 women were treated with 75 mg of melatonin nightly for 4 years.[145]

 

[s1mpleman]

Very interesting thanks for sharing. I've only gone up to 9mg which was taking in 3 pills back when I was first getting myself off pot to help me sleep. I found all it did then was make me really jittery but 1mg seemed to be perfect. I've found I can sleep without it totally fine now, but I get a much deeper sleep with it. It helped a lot at resetting my sleeping patterns too, it's a godsend when I have to travel to Brazil to see the wifes family.

I never considered a higher dose at all although I've heard quite a lot it isn't toxic at any level.

Thought I'd have a quick search through pubmed and found some interesting studies. One that even experimented with intravenous administration up till 100mg. Hope there helpful, I'm pretty astonished by the results.

Neuroprotective effects of high-dose vs low-dose melatonin after blunt sciatic nerve injury - PubMed

Our results suggest that melatonin, especially at a dose of 50 mg/kg, has a potent neuroprotective effect and can preserve peripheral neural fibers from lipid peroxidative damage after blunt trauma. With further investigations, we hope that these data may prove useful to clinicians who treat...

www.ncbi.nlm.nih.gov

Abstract
INTRODUCTION:
Melatonin, the secretory product of the pineal gland, has potent antioxidant properties. The aim of this study was to compare the effects of low-dose (10 mg/kg) vs high-dose (50 mg/kg) melatonin on early lipid peroxidation levels and ultrastructural changes in experimental blunt sciatic nerve injury (SNI). We believe this to be the first study to assess the dose-dependent neuroprotective effects of melatonin after a blunt peripheral nerve injury.
MATERIALS AND METHODS:
Rats were randomly allocated into 5 groups of 10 animals each. The SNI only rats underwent a nerve injury procedure. The SNI plus vehicle group received SNI and intraperitoneal injection of vehicle (diluted ethanol) as a placebo. The SNI plus low-dose or high-dose melatonin groups received intraperitoneal melatonin at doses of 10 mg/kg or 50 mg/kg, respectively. Controls had no operation, melatonin or vehicle injection. SNI was induced by clamping the sciatic nerve at the upper border of the quadratus femoris for 2 min.
RESULTS:
Sciatic nerve samples were harvested 6 h after nerve injury and processed for biochemical and ultrastructural analysis. Trauma increased the lipid peroxidation of the sciatic nerve by 3.6-fold (153.85 +/- 18.73 in SNI only vs 41.73 +/- 2.23 in control rats, P < 0.01). Low (P = 0.02) and high (P < 0.01) doses of melatonin attenuated the nerve lipid peroxidation by 25% and 57.25%, respectively (65.76 +/- 2.47 in high-dose vs 115.08 +/- 7.03 in low-dose melatonin groups).
DISCUSSION:
Although low-dose melatonin reduced trauma-induced myelin breakdown and axonal changes in the sciatic nerve, high-dose melatonin almost entirely neutralized any ultrastructural changes.
CONCLUSION:
Our results suggest that melatonin, especially at a dose of 50 mg/kg, has a potent neuroprotective effect and can preserve peripheral neural fibers from lipid peroxidative damage after blunt trauma. With further investigations, we hope that these data may prove useful to clinicians who treat patients with nerve injuries.

Pharmacokinetics of high-dose intravenous melatonin in humans - PubMed

This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0...

www.ncbi.nlm.nih.gov

This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221,500.0 (185,637.5-326,175.0) pg/mL and 1,251,500.0 (864,375.0-1,770,500.0) pg/mL, respectively; mean (SD) t1/2 was 42.3 (5.6) minutes and 46.2 (6.2) minutes; mean (SD) Vd was 1.6 (0.9) L/kg and 2.0 (0.8) L/kg; mean (SD) CL was 0.0253 (0.0096) L/min · kg and 0.0300 (0.0120) L/min · kg; and median (IQR) AUC0- ∞ , 8,997,633.0 (6,071,696.2-11,602,811.9) pg · min/mL and 54,685,979.4 (36,028,638.6-105,779,612.0) pg · min/mL. High-dose intravenous melatonin did not induce sedation, evaluated as simple reaction times. No adverse effects were reported in the study.

The use of high-dose melatonin in liver resection is safe: first clinical experience - PubMed

Experimental data suggest that melatonin decreases inflammatory changes after major liver resection, thus positively influencing the postoperative course. To assess the safety of a preoperative single dose of melatonin in patients undergoing major liver resection, a randomized controlled...

www.ncbi.nlm.nih.gov

Abstract
Experimental data suggest that melatonin decreases inflammatory changes after major liver resection, thus positively influencing the postoperative course. To assess the safety of a preoperative single dose of melatonin in patients undergoing major liver resection, a randomized controlled double-blind pilot clinical trial with two parallel study arms was designed at the Department of General and Transplantation Surgery, Ruprecht-Karls-University, Heidelberg. A total of 307 patients, who were referred for liver surgery, were screened. One hundred and thirteen patients, for whom a major liver resection (≥3 segments) was scheduled, were eligible. Sixty-three eligible patients refused to participate, and therefore, 50 patients were randomized. A preoperative single dose of melatonin (50 mg/kg BW) dissolved in 250 mL of milk was administered through the gastric tube after the intubation for general anesthesia. Controls were given the same amount of microcrystalline cellulose. Primary endpoint was safety. Secondary endpoints were postoperative complications. Melatonin was effectively absorbed with serum concentrations of 1142.8 ± 7.2 ng/mL (mean ± S.E.M.) versus 0.3 ± 7.8 ng/mL in controls (P < 0.0001). Melatonin treatment resulted in lower postoperative transaminases over the study period (P = 0.6). There was no serious adverse event in patients after melatonin treatment. A total of three infectious complications occurred in either group. A total of eight noninfectious complications occurred in five control patients, whereas three noninfectious complications occurred in three patients receiving preoperative melatonin (P = 0.3). There was a trend toward shorter ICU stay and total hospital stay after melatonin treatment. Therefore, a single preoperative enteral dose of melatonin is effectively absorbed and is safe and well tolerated in patients undergoing major liver surgery.

The effect of high dose melatonin on cardiac ischemia- reperfusion Injury - PubMed

Our study suggests that high dose melatonin, appears to offer protection against cardiac ischemia-reperfusion injuries in rats by scavenging the free radicals and could have a potential clinical use in the management of myocardial ischemia.

www.ncbi.nlm.nih.gov

Abstract
PURPOSE:
Melatonin, the most potent scavenger of toxic free radicals, has been found to be effective in protecting against pathological states due to the release of reactive oxygen species. This study was performed to establish the effect of high dose melatonin on protection against ischemia- reperfusion (I/R) injury in rat hearts.
MATERIALS AND METHODS:
Forty male Sprague-Dawley rats were used in this study. They were separated into four groups of ten rats each. A left coronary artery occlusion was induced in the rats by ligating the artery for 20 minutes and then releasing the ligation (reperfusion) afterwards. The control group was Group A. Group B was subjected to myocardial ischemia-reperfusion without any treatment, while Group C underwent myocardial ischemia-reperfusion with a melatonin treatment before the ischemia. Group D was subjected to myocardial ischemia-reperfusion with a melatonin treatment before the reperfusion. After 20 minutes of reperfusion, blood samples were obtained from each group for biochemical studies, and the animals were sacrificed for histological and, immunohistochemical examinations of the myocardial tissue.
RESULTS:
We found that the cardiac troponin T(cTn-T) levels were significantly increased in Group B when all groups were compared. In the Group C rats treated with melatonin, the cTn-T values were significantly lower than those in Groups B and D. In addition, malondialdehyde (MDA) and antioxidant enzymes including, superoxide dismutase (SOD) and myeloperoxidase (MPO) were lower than those in Group B in the melatonin treated groups. The differences were statistically significant (p < 0.05). Histopathologic and immunohistopathologic studies also supported the effectiveness of melatonin.
CONCLUSION:
Our study suggests that high dose melatonin, appears to offer protection against cardiac ischemia-reperfusion injuries in rats by scavenging the free radicals and could have a potential clinical use in the management of myocardial ischemia.

 

[s1mpleman]

Just found two more to add.

The first they found a reduction in oxidative damage from ALS and the second one deals with melatonin and radiation therapy.

Reduced oxidative damage in ALS by high-dose enteral melatonin treatment - PubMed

Amyotrophic lateral sclerosis (ALS) is the collective term for a fatal motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression. Melatonin is an amphiphilic molecule with a unique spectrum of antioxidative effects not conveyed by...

www.ncbi.nlm.nih.gov

Abstract
Amyotrophic lateral sclerosis (ALS) is the collective term for a fatal motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression. Melatonin is an amphiphilic molecule with a unique spectrum of antioxidative effects not conveyed by classical antioxidants. In preparation of a possible future clinical trial, we explored the potential of melatonin as neuroprotective compound and antioxidant in: (1) cultured motoneuronal cells (NSC-34), (2) a genetic mouse model of ALS (SOD1(G93A)-transgenic mice), and (3) a group of 31 patients with sporadic ALS. We found that melatonin attenuates glutamate-induced cell death of cultured motoneurons. In SOD1(G93A)-transgenic mice, high-dose oral melatonin delayed disease progression and extended survival. In a clinical safety study, chronic high-dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS.

Randomized phase II trial of high-dose melatonin and radiation therapy for RPA class 2 patients with brain metastases (RTOG 0119) - PubMed

High-dose melatonin did not show any beneficial effect in this group of patients.

www.ncbi.nlm.nih.gov

Abstract
PURPOSE:
To determine if high-dose melatonin for Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) Class 2 patients with brain metastases improved survival over historical controls, and to determine if the time of day melatonin was given affected its toxicity or efficacy. RTOG 0119 was a phase II randomized trial for this group of patients.
METHODS AND MATERIALS:
RTOG RPA Class 2 patients with brain metastases were randomized to 20 mg of melatonin, given either in the morning (8-9 AM) or in the evening (8-9 PM). All patients received radiation therapy (30 Gy in 10 fractions) in the afternoon. Melatonin was continued until neurologic deterioration or death. The primary endpoint was overall survival time. Neurologic deterioration, as reflected by the Mini-Mental Status Examination, was also measured.
RESULTS:
Neither of the randomized groups had survival distributions that differed significantly from the historic controls of patients treated with whole-brain radiotherapy. The median survivals of the morning and evening melatonin treatments were 3.4 and 2.8 months, while the RTOG historical control survival was 4.1 months.
CONCLUSIONS:
High-dose melatonin did not show any beneficial effect in this group of patients.

 

[Mrs. Peel]

Finally, animal studies have shown that moderately large doses of melatonin (equivalent in one study to about 30 mg in adult humans) increased light-induced damage to retinal photoreceptors

Um, does this mean that if you have light sensitivity (or damage to retinal photoreceptors) that taking melatonin makes it worse?