High Dose Melatonin Therapy

[Keyhole]

Because of extreme light sensitivity and a lot of other eye issues, I do not go outside without sunglasses, nor do I stand by windows unless it is very dim out so I do not get direct sun(light) into my eyes. I was told (and take with a grain of salt but it makes sense) by an energy reader that my body is hardly making melotonin, and to take 3 mg of sublingual melatonin before bed and also another 3 mg time-release tablet to try and keep me asleep throughout the night (I wake up about 5-6 times each night). It doesn't work so I upped the sublingual dose before bed to 5 mg and I still wake up. I already sleep in a dark room, have a humidifier, use earplugs, stay away from electronics, and have tried every sleep trick and supplement known to man.

Perhaps I should try taking a higher a dose of melatonin at night? Or maybe start taking some during the day also?

Do you wear blue/green blocking glasses? That is a sure-fire way to facilitate melatonin production. The research supports it, and I personally cannot sleep without them. I am extremely sensitive to blue light at night time, and have a history of sleep problems. Since I have been religious with blocking blue light at night, sleep is pretty much perfect each night (7-10 minutes until falling asleep, no waking in the night, mostly waking feel refreshed).

I had one client who was on the max dose of zoplicone for two decades and still had difficulty sleeping... she was a self-proclaimed "night owl". She started using blue blockers and within one month was completely off all sleep medication. Funnily enough, she is now a self-proclaimed "early bird".

FWIW, sensitivity to light in the daytime points to problems with riboflavin. You could try 2-300mg per day for a month and see if that helps. I find many people's daylight sensitivity disappears with riboflavin.

P.S - Sorry for posting about things not related to melatonin - I do not want to derail the thread!

 

[Keyhole]

trendsetter37

I noticed that if I do an aggressive aerobic exercise in the mornings it would clear the headache and improve the circulation to the brain. So it maybe that melatonin reduces blood flow to the brain which induces sleep. A possible explanation for this side affect.

I too have stopped taking it on a regular basis and only take it when I have a few night of poor quality of sleep.

Melatonin is a neurotransmitter and is not a hormone which does reduce its risk of harm.

Melatonin is both a neurotransmitter and a hormone - which means it readily travels through the bloodstream and acts on tissues/cells that way, but at the same time is used as a neurotransmitter at synapses to exert different effects.

RE blood flow, melatonin does not appear to alter cerebral blood flow. It does have effects on the kidneys and other organs to some extent, but not the brain as per the current research:

Melatonin differentially affects vascular blood flow in humans

Melatonin is synthesized and released into the circulation by the pineal gland in a circadian rhythm. Melatonin has been demonstrated to differentially alter blood flow to assorted vascular beds by the activation of different melatonin receptors in animal models. The purpose of the present study was to determine the effect of melatonin on blood flow to various vascular beds in humans. Renal (Doppler ultrasound), forearm (venous occlusion plethysmography), and cerebral blood flow (transcranial Doppler), arterial blood pressure, and heart rate were measured in 10 healthy subjects (29 ± 1 yr; 5 men and 5 women) in the supine position for 3 min. The protocol began 45 min after the ingestion of either melatonin (3 mg) or placebo (sucrose). Subjects returned at least 2 days later at the same time of day to repeat the trial after ingesting the other substance.

Melatonin did not alter heart rate and mean arterial pressure. Renal blood flow velocity (RBFV) and renal vascular conductance (RVC) were lower during the melatonin trial compared with placebo (RBFV, 40.5 ± 2.9 vs. 45.4 ± 1.5 cm/s; and RVC, 0.47 ± 0.02 vs. 0.54 ± 0.01 cm·s−1·mmHg−1, respectively). In contrast, forearm blood flow (FBF) and forearm vascular conductance (FVC) were greater with melatonin compared with placebo (FBF, 2.4 ± 0.2 vs. 1.9 ± 0.1 ml·100 ml−1·min−1; and FVC, 0.029 ± 0.003 vs. 0.023 ± 0.002 arbitrary units, respectively). Melatonin did not alter cerebral blood flow measurements compared with placebo. Additionally, phentolamine (5-mg bolus) after melatonin reversed the decrease in RVC, suggesting that melatonin increases sympathetic outflow to the kidney to mediate renal vasoconstriction. In summary, exogenous melatonin differentially alters vascular blood flow in humans. These data suggest the complex nature of melatonin on the vasculature in humans.

As per my understanding, melatonin's sleep-promoting effects are due to several mechanisms, A recent paper indicated that melatonin has inhibitory effects on brain regions referred to as "default mode networks" which can induce fatigue and sleepiness. However, melatonin is also involved in the regulation of gene expression that follows a circadian cycle (CLOCK genes etc), which influence the overall milieu of hormones/neurotransmitters/cell functions. So the authors say that this is probably the main way that is it promoting sleep :

New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation

In humans and other diurnal species, melatonin acts at the SCN to attenuate the wake‐promoting signal of the circadian clock, thus promoting sleep (Liu et al., 1997). In addition, melatonin acts at the default mode network (DMN) regions in the brain to promote fatigue and sleep‐like changes in activation of the precuneus (Gorfine et al., 2006; Gorfine and Zisapel, 2009). The DMN is a network of brain regions that is active during rest in the absence of task‐dependent performance (Raichle et al., 2001). It consists of the medial prefrontal cortex, posterior cingulate cortex and precuneus, inferior parietal lobe, lateral temporal cortex and hippocampal formation and is involved with interoceptive awareness and mind wandering (Spreng et al., 2010).


Within this network the precuneus is involved in a variety of complex functions, which include recollection and memory, integration of information (gestalt) relating to perception of the environment, cue reactivity, mental imagery strategies, episodic memory retrieval and affective responses to pain (Cavanna and Trimble, 2006). While asleep, connectivity within the DMN decreases and is diminished during SWS (Horovitz et al., 2009). Melatonin given in the afternoon to healthy young individuals attenuates activation in the precuneus, located at the rostro‐medial aspect of the occipital cortex (Figure 1A). These effects correlate with subjective measurements of fatigue (Gorfine et al., 2006). However, activation of this brain area is decreased concomitantly with the endogenous rise of melatonin, so that administration of exogenous melatonin at night does not have a further notable effect (Figure 1B,C). Because melatonin does not increase the amount of SWS (Arbon et al., 2015), which is considered a marker of the homeostatic sleep pressure (Zisapel, 2007), the sleep promoting effects of melatonin may be mostly ascribed to the circadian component of sleep regulation.

BPS Publications

bpspubs.onlinelibrary.wiley.com

 

[Anamarija]

I read the NCBI paper carefully and it appears that it is best to start taking the doses in the afternoon, at least, and then take several before bedtime. Like starting with 10 mg at 3 pm, 10 at 6, 10 at 9 pm. Then, the next day, double the dose, and go up to say 50 mg each dose. They say do something like this for 3 or 4 weeks on and then take a week off. But that's for severe things like AIDS, so maybe less severe conditions would require only a week or so? There are a lot of papers listed as sources for that one, but I haven't read them. But it sure seems that a lot of things can get fixed pretty easily this way.

I'm taking melatonin for years, but only very small doses (1mg) in the evening, just before a sleep. Before melatonin I had a big issues with sleeping, sometimes I couldn't get enough sleep for months. But, even I sleep all night without waking up I usually wake up grumpy and have a feeling of heaviness. I need at least two hours with coffee and silence just to wake up. Every sound (like a cat meowing) is annoying to me. Maybe this has nothing to do with melatonin, maybe I'm just grumpy person in the morning but I'm wiling to try taking this high dose of melatonin. I'm interested to see how bigger dose will have affect on me. I hope not more grumpiness .

 

[Laura]

There's a slew of papers referenced in the NCBI paper linked above and they might be available for free. Perhaps some of you medically informed folks could look over that list and check out some of the ones that sound interesting and report on them? Details are needed!

 

[NewEngland Seeker]

What's your source for this statement? A quick duckduckgo.com search showed the top listings describing it as a horomone.

Melatonin is both a neurotransmitter and a hormone

I had known that melatonin was a hormone but did a google search to verify.

From search:------------------
Melatonin is a ubiquitous natural neurotransmitter-like compound produced primarily by the pineal gland. This agent is involved in numerous aspects of the biological and physiologic regulation of body functions. ... Melatonin is a widely occurring neurotransmitter-like compound derived primarily from the pineal gland.
---------------------------------

As far as brain blood flow I am only reporting my self observations and I do notice a subtle decrease. It is not objectivily verified but it seems to explain my unpleasant response to it. There maybe another reason for this but so far I am not able to connect anything else to my headaches and slowness of mental functions from melatonin. Reading the research articles would indicate that my response is a variant not the norm.

 

[Andrian]

Interesting find, thank you Laura for sharing. Yesterday night just for the sake of curiosity i've taken 10 mg of melatonin. I slept good, waked a couple of times during the night but only for a couple of seconds. The most interesting thing that happen is that i had a very vivid dream that i was able to remember after waking up. I even can't remember when it was the last time i remembered what i was dreaming and believe me i'm not exaggerating. For me it's a topic worth exploring, so i'll keep taking at least 10 mg and see how it will go.

 

[Gaby]

"Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action" published in 2018 in BMC Medicine seems to say that even though melatonin might increase inflammatory molecules in those with autoimmune diseases, melatonin is still pretty safe with benefits outweighing adverse effects. Some relevant quotes:

Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action - PMC

Our aims were to evaluate critically the evidence from systematic reviews as well as narrative reviews of the effects of melatonin (MLT) on health and to identify the potential mechanisms of action involved. An umbrella review of the evidence across ...

www.ncbi.nlm.nih.gov

However, caution is advised for the use or supplementation of MLT in some autoimmune conditions, such as rheumatoid arthritis, asthma or organ transplantation as MLT has been reported to stimulate the function of the immune system via the production of interleukins (IL-1, IL-2, IL-6 and IL-12), interferon γ (IFN-γ), Th cells, cytotoxic T cells, and B- and T-cell precursors

Some of the effects of MLT [melatonin] are via anti-oxidative (e.g. [45–49]), anti-inflammatory (e.g. [50–52]), anti-apoptotic (e.g. [53, 54]), anti-nociceptive (e.g. [33, 55]), anti-hypertensive (e.g. [56–58]), cytoprotective, neuroprotective, cardioprotective or nephroprotective effects (e.g. [59–64]), and by enhancing mitochondrial function and protecting nuclear and mitochondrial DNA or regulating homeostasis (e.g. [53, 65]; Table 1).

AEs [adverse effects] of exogenous MLT and MLT analogues were reported in 11 (5.6%) of the included reviews

. Two reviews pooled the safety data [40, 66]. In Liu and Wang [40], there were more subjective reports of at least one AE after treatment with ramelteon compared to placebo (RR = 1.11, 1.03 to 1.20, P < 0.01; seven studies). In Huang et al. [66], however, agomelatine revealed a lower rate of discontinuation due to AEs compared with selective serotonin reuptake inhibitors or serotonin–norepinephrine reuptake inhibitors (RR = 0.38, 95% CI = 0.25 to 0.57). AEs were typically mild and included worsening of symptoms (seizures, asthma or headaches), transient headaches and dizziness, abdominal pain, pharyngitis, back pain and asthenia, somnolence, fatigue, nasopharyngitis, upper respiratory infection, nausea, dizziness, diarrhoea, dyspepsia, dysmenorrhoea, diarrhoea, dry mouth, increased alanine aminotransferase, nightmares, morning drowsiness, enuresis, rash and hypothermia (Additional file 5: Table S5). Given the overwhelming benefits of MLT treatment and the existence of very few and mild AEs (also for long-term use), the risk–benefit ratio favours MLT.

Keep in mind that the relatively low incidence of adverse effects above includes those for melatonin analogues (synthesized pharmaceuticals) used in mainstream medicine for depression as well.

 

[Gaby]

"Melatonin: Countering Chaotic Time Cues published" in Frontiers in Endocrinology in 2019 highlights the research for right timing of dosage and also some concerns in people who are genetically predisposed to develop metabolic syndrome with high doses of melatonin (carriers of a gene variant), especially if they take melatonin during the day. The rest sounds pretty interesting. Again, dosage is not widely discussed except briefly for a cancer study where they used 300mg of melatonin.

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.

Melatonin: Countering Chaotic Time Cues - PMC

Last year melatonin was 60 years old, or at least its discovery was 60 years ago. The molecule itself may well be almost as old as life itself. So it is time to take yet another perspective on our understanding of its functions, effects and clinical ...

www.ncbi.nlm.nih.gov

The Entero-Insular Axis and Diabetes

The importance of rhythms to the entero-insular axis was also evident early on, with variations in glucose tolerance and insulin sensitivity (166). The subject has been very recently reviewed (161). The circadian, SCN-driven nature of these rhythms is now well established alongside the “masking” effects of mealtimes, meal content and other external inputs (167, 168). Triacylglycerol (TAG) has a particularly marked circadian rhythm in constant routine (167). During both simulated and real shift work, standard meals taken at inappropriate times at night—biological night when melatonin secretion is high-lead to evidence of insulin resistance/glucose intolerance and higher TAG, both risk factors for heart disease (167, 169). This is therefore one possible mechanism underlying the epidemiological data showing higher risk of these major diseases.

Circadian re-adaptation in real shift workers resolves some metabolic risk factors (169) (and see Gibbs M, Hampton SH, Morgan L, Arendt J. Effect of shift schedule on offshore shift workers' circadian rhythms and health, 2004. RR318 - Effect of shift schedule on offshore shiftworkers'...). So there is good reason to use the chronobiotic properties of melatonin (and timed light exposure) to manipulate circadian phase. It remains to be determined to what extent central and peripheral oscillators remain in synchrony/coupled in these circumstances.

Melatonin clearly influences glucose concentrations- pinealectomy leads to increased glucose in nocturnal rats (170). In MT1 and MT2 receptor knockout mice the SCN-driven glucose rhythm is abolished independently of peripheral oscillators in muscle, adipose tissue and liver (171). In humans in one study, the decrease in glucose tolerance from morning to evening was mostly influenced by the endogenous circadian system compared to the sleep-wake cycle. However, in apparent contrast to pinealectomy effects in animals, melatonin administered during day time just prior to a glucose tolerance test in healthy adults clearly impaired glucose tolerance both in the morning and the evening (172, 173), an effect that was dependent on a common gain-of-function variant of the melatonin receptor gene MTNR1B151 (see below). Melatonin may also acutely decrease insulin secretion in cultured human islets (174). Thus, some controversy exists in the literature especially when comparing results in nocturnal rodents with diurnal humans with both beneficial and detrimental effects of melatonin reported. It is intriguing to note that the rare condition 'familial insulin resistance' or Rabden-Mendenhall syndrome is associated with pineal hyperplasia (175, 176).

In view of pre-existing associations of the pineal and melatonin with metabolic function the discovery of related MT1 and MT2 receptor variants aroused enormous interest. 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. Some controversies have arisen and have been reviewed (181). The question is not solved.

 

[Gaby]

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.

Hypotheses: melatonin/steroid combination contraceptives will prevent breast cancer - PubMed

The use of the conventional combination oral contraceptives (containing ethinyl-estradiol and a progestin) is associated with reduced risk of ovarian and endometrial cancer. However, prolonged use of these pills before first term pregnancy apparently increases the risk of pre menopausal breast...

www.ncbi.nlm.nih.gov

Study protocol
Twenty-eight women (study A) were followed during 1 prestudy
control cycle, 4 medication months, and 2 poststudy
control cycles. Cycle evaluations included BBT, LH, FSH,
estradiol (EJ, and progesterone (P,) estimates. Prestudy cycle
evaluation included BBT. Hormone determinations were performed
in the first and fourth medication months, daily in the
midcycle period (days 12-16), and every 3 days during the
remaining days of the cycle. In the second and third medication
months and the 2 poststudy control cycles, blood was collected
once in the luteal phase (days 20-24) only. Four women were
medicated with 300 mg MEL during days 5-17 of the cycle, and
8 women with 300 mg MEL daily (days l-30). In addition,
MEL was combined with the synthetic progestin NET. Groups
of 4 women were medicated with 0.75 mg NET in combination
with 300, 75, or 7.5 mg MEL. Four women were treated with
75 mg MEL combined with 0.3 mg NET. MEL/NET medications
were administered for 21 days, followed by 7 pill-free
days. In a second protocol (study B), 4 women were treated for
2 months, with 1 pre- and 1 poststudy control cycle. Two women
were treated with 300 mg MEL on days 1-21, and 2 women
with 300 mg MEL combined with 0.15 mg NET on days 1-21
(Table 1). The study setup was similar to the protocol of study
A; however, blood samplinga nd hormone measurementsw ere
performed in ail study months. In addition, transvaginal ultrasound
examinations were performed during the prestudy control
cycle and the 2 medication months. Prestudy physical
examination, electrocardiogram, hematology, biochemistry,
and urine analysis were repeated in the last medication month
and in the last poststudy control cycle. In addition, 8 regularly
cycling women (mean cycle length, 27.8 days; range, 25-31
days) were sampled daily as controls (18). The subjects completed
a weekly questionnaire, which included 15 structured
questions related to menstrual, physical, and emotional wellbeing.

There were no complaints about altered night/
day, sleep, and activity patterns, altered emotional wellbeing,
or mood changes. The results of all hematological
and biochemical determinations were normal before, during,
and after treatment (data not shown).

 

[Gaby]

"A Review of the Multiple Actions of Melatonin on the Immune System" published in 2005 in Endocrine has very interesting information. Melatonin's controversial use is most clearly related in those afflicted with Rheumatoid Arthritis. The use of melatonin in other autoimmune diseases remains controversial, i.e. Crohn's disease, lupus, and multiple sclerosis. Again, particular doses are not highlighted. It is interested to know that melatonin seems to have an anti-viral effect (remember that one!) and is protective in septic shock.

Melatonin and Infection

Evidence of melatonin’s ability to protect against viral encephalitis
was provided by Maestroni et al. (88), who showed
that it prevented paralysis and death in mice infected with
encephalomyocarditis virus (EMCV) after acute stress. Ben-
Nathan et al. (182) also reported that the administration of
melatonin reduced viremia and significantly postponed the
onset of the disease and death in mice infected with the lethal
Semliki Forest virus (SFV) and attenuated non-invasive
West Nile virus (WNV). Similar changes occur in mice
infected with Venezuelan equine encephalomyelitis virus
(VEEV), where melatonin delays the onset of the disease
and reduce mortality (183–185). Zhang et al. (186) also reported
that treatment with dehydroepiandrosterone or melatonin,
alone or in combination, prevented the reduction of
B- and T-cell proliferation and the Th1 cytokine secretion in
mice with acquired immune-deficiency syndrome (AIDS)
caused by LP-BM5 leukemia retrovirus. Melatonin also suppressed
the elevated production of Th2 cytokines, reduced
hepatic lipid peroxidation, and prevented the loss of vitamin
E.

Melatonin and Inflammation

In the last decade, melatonin has also been shown to play
an important role in immunopathological conditions such
as acute and chronic inflammation (187–189). Septic shock
is a systemic response which can be caused by bacterial
endotoxins such as LPS which through an interaction with
receptors on the surface of a variety of host cells induce the
generation of numerous pro-inflammatory factors such as
TNF-, IL-1, IL-6, IL-12, IFN-, and NO (190). Most
studies relating to melatonin and endotoxin-induced processes
observed that administration of melatonin improves
the survival of mice and rats from a lethal dose of LPS with
survival rate higher than 80% (191–193). In this context,
melatonin has been shown to prevent endotoxic-induced
circulatory failure in rats through an inhibition of TNF-
levels (193) and to reduce postshock levels of IL-6 in male
C3H/HeN mice (194). Moreover, a vast amount of evidence
has shown that melatonin counteracts LPS-induced expression
of inducible and mitochondrial nitric oxide synthase
(iNOS and mtNOS) as well as decrease NO levels in mice
and rats (195,196). Furthermore, the melatonin abolishes
the LPS-induced rise in lipid peroxidation in both in vivo
and in vitro inflammation models (197,198). Furthermore,
a clinical study has shown that abnormalities in the circadian
melatonin secretion in septic patients are mainly related
to the presence of severe sepsis (199). Melatonin also modulates
allergic lung inflammation by improving the ability
of cells to migrate from the bone marrow to the bronchoalveolar
fluid (200). In newborn infants as well, melatonin
has been shown to improve clinical outcome and prevent
death due to septic shock (201).

Melatonin and Autoimmunity

It must be noted that the pharmacological effect of melatonin
on the immune response may not always be beneficial.
Thus, the role of melatonin on the autoimmune disease
rheumatoid arthritis (RA) seems to be negative, although in
others such as multiple sclerosis and lupus its effects are
still controversial.
In an autoimmune arthritis model developed in mice and
rats, melatonin administration induces a more severe arthritis.
Accordingly, pinealectomy reduced the severity of the
arthritis by a slower onset of the disease, a less severe course
of the disease, and reduced serum levels of anticollagen II
antibodies; conversely, melatonin administration exacerbated
inflammation in young rats injected with FCA (202).
Thus, factors that enhance endogenous melatonin production
might play a role in the etiology of RA.
It is interesting to note that the geographical distribution
of RA shows a north–south gradient, with higher latitudes
being associated with an increased incidence and severity
of RA (203). The increased season-associated variability
in the photoperiod might mean enhanced melatonin production
especially during the long winter nights. In addition,
the clinical symptoms of RA show a circadian variation
with joint stiffness and pain being more prominent in the
early morning. Consistently, human proinflammatory cytokine
production exhibits a diurnal rhythmicity with peak
levels during the night and early morning at a time when
plasma cortisol is lowest (204). Consequently, the clinical
symptoms of RA might be related to the circadian rhythm
of melatonin synthesis and release.
One clinical study strongly supports a close relationship
between melatonin production and IL-12 and NO production
by macrophages from RA patients (205). Other authors
also found that RA patients have higher nocturnal serum
concentration of melatonin than healthy controls. Another
interesting observation was that macrophages infiltrating
the synovial fluid of RA patients showed specific melatonin
binding sites and melatonin was also present at high
concentrations in the synovial fluid (206). Although most
studies suggest that melatonin might play a promoting role
in rheumatoid arthritis, recently it was noted that melatonin
administration inhibits the inflammatory response in a model
of adjuvant-induced arthritis in rats (207),
Another serious autoimmune disease that might be related
to melatonin is multiple sclerosis (MS). As the distribution
of people with MS is greater in higher latitudes, shorter
winter days could be an environmental factor involved in
the etiology of this disease. It has been observed that a melatonin
receptor antagonist, luzindole, suppresses experimental
allergic encephalomyelitis (EAE), the animal model
of MS (208). However, other authors have found that neither
winter-type short days nor melatonin supplementation
influence the development or severity of the disease (209).
Even the beneficial role of melatonin has been described in
EAE induced in Lewis rats (210). Moreover, it has been
reported that while neonatally pinealectomized Wistar rats
develop extensive pathological changes and severe neurologic
deficits upon induction of EAE, when rats were pinealectomized
at 6 wk of age they appeared resistant to the induction
of EAE. This age-related susceptibility suggests that
the viral infection that seem associated with the development
of MS is most likely acquired in infancy prior to the
establishment of the melatonin circadian rhythm (between
3 and 9 mo of age in humans) (211).

The role of melatonin in lupus erythematosus (SLE) is
unclear, while the first published work reported a significantly
enhancement in the survival of female NZB/W lupus
mice when melatonin injections were given in the morning
versus afternoon (212), subsequent studies have not observed
a clear correlation between disease activity and melatonin
levels either in humans and in lupus-prone MRL/MPfas(
Ipr) mice (213,214).
In 2002, Calvo et al. (215) published a letter where they
hypothesized how melatonin, through the activation of IL-
12 by monocytes and the subsequent increase of IFN-,
exacerbated the symptoms of Crohn’s disease in a 35-yr-old
woman.

 

[Gaby]

Melatonin Supplementation, a Strategy to Prevent Neurological Diseases through Maintaining Integrity of Blood Brain Barrier in Old People

Melatonin Supplementation, a Strategy to Prevent Neurological Diseases through Maintaining Integrity of Blood Brain Barrier in Old People - PMC

Blood brain barrier (BBB) plays a crucial role in maintaining homeostasis of microenvironment that is essential to neural function of the central nervous system (CNS). When facing various extrinsic or intrinsic stimuli, BBB is damaged which is an ...

www.ncbi.nlm.nih.gov

Blood brain barrier (BBB) plays a crucial role in maintaining homeostasis of microenvironment that is essential to neural function of the central nervous system (CNS). When facing various extrinsic or intrinsic stimuli, BBB is damaged which is an early event in pathogenesis of a variety of neurological diseases in old patients including acute and chronic cerebral ischemia, Alzheimer’s disease and etc. Treatments that could maintain the integrity of BBB may prevent neurological diseases following various stimuli. Old people often face a common stress of sepsis, during which lipopolysaccharide (LPS) is released into circulation and the integrity of BBB is damaged. Of note, there is a significant decrease of melatonin level in old people and animal. Melatonin has been shown to preserves BBB integrity and permeability via a variety of pathways: inhibition of matrix metalloproteinase-9 (MMP-9), inhibition of NADPH oxidase-2, and impact on silent information regulator 1 (SIRT1) and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. More important, a recent study showed that melatonin supplementation alleviates LPS-induced BBB damage in old mice through activating AMP-activated protein kinase (AMPK) and inhibiting gp91phox, suggesting that melatonin supplementation may help prevent neurological diseases through maintaining the integrity of BBB in old people.

They don't risk suggesting a particular dose though.

 

[Oxajil]

Very interesting, thanks for sharing! A few more papers:

The effect of high dose melatonin on cardiac ischemia-reperfusion Injury (FYI: ischemia-reperfusion injury is: tissue damage caused when blood supply returns to tissue after a period of ischemia or lack of oxygen)

• This study showed that high dose melatonin offered protection against this injury by "scavenging the free radicals and could have a potential clinical use in the management of myocardial ischemia"
• The test subjects were rats, however. The rats that received melatonin, received 50 mg/kg i.p, Sigma, M-5250, St. Louis, MO, USA. (I'm guessing that's where they got their melatonin from)

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

• Researchers conclude: 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.
• Rats were also used in this study: The SNI plus low-dose or high-dose melatonin groups received intraperitoneal melatonin at doses of 10 mg/kg or 50 mg/kg, respectively.

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

• Their whole abstract is worth posting I think: 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.
• More info from the paper itself: Patients were treated for 11.5 ± 1.2 (2–24) months. Rectal application immediately achieved high plasma and urinary melatonin levels, but still maintained–at a higher niveau–a day/night pattern (Fig. 4A and suppl. Fig. 3). Follow-up analysis after 2 months showed that melatonin plasma levels stayed in the expected range, indicating that continuous melatonin administration does not lead to accumulation or increased metabolism. No adverse effects were observed nor reported. Mean routine laboratory data remained essentially unchanged. Several parameters showed typical fluctuations, e.g., associated with physical stress or intercurrent infections (creatine kinase or leucocytes), but none of them likely to be related to melatonin. In two cases, the discontinuation of riluzole revealed that temporarily increased transaminase values were the result of riluzole rather than melatonin. Some patients reported initially faster sleep onset (n = 5), improved sleep quality (n = 15), and better sleep continuation (n = 3), while others did not find their sleep changed (n = 14). No signs of hangover or increased fatigue during daytime were noted. Melatonin medication was well accepted by patients, and only eight discontinued treatment: five at the end stage, three with extremely rapidly progressing disease, who refused any medication. A total of 13 patients died (respiratory failure), most of them entering the safety study at an advanced disease stage (mean ALSFRS upon entry 23.6 ± 1.8; range 12–31). The ALSFRS scores from study entry to 1 yr of follow-up for all patients (n ¼ 31) are presented in Fig. 4B.
• The patients received the high dose melatonin in the evening.

To summarize, two studies with rats showed that high dose melatonin protected against tissue damage and nerve injury, respectively, and one study with patients with sporadic ALS showed high dose melatonin improved sleep for some (onset, quality, and continuation) and reduced oxidative stress levels. So all these results point to the neuroprotective properties of high dose melatonin as also noted before in this thread. I wonder why the researchers opted for rectal application of melatonin as done in the third study with patients (does it yield better results?). All-in-all quite interesting. Never thought that such a high dose of melatonin (300mg/day!!) would have such effects. But of course, caution is important. FWIW.

 

[goyacobol]

Thanks for the posts indicating even Autoimmunity properties and blood-brain barrier aspects of melatonin.

I use 5 mg in the evenings and it seems to help some with sleep.

I just thought I would list some Cs comments on some of the effects of melatonin which don't seem to show up in most current research.

Session 28 October 1994:

Q: (L) Why should we take the Melatonin?

A: Is mild hallucinogen.

Q: (L) Why do we need this?

A: Keeps exercising psychic abilities and opens paths. Don't be alarmed by vividly erotic dreams.

Q: (L) Should we expect to have vividly erotic dreams?

A: Possible as psyche passes through levels on ascension.

Session 16 November 1994:

Q: (L) When L__ took the Melatonin the other night, how come he was unable to sleep?

A: Adjusting to the melatonin.

Want to remember dreams better? Melatonin may help.

Session 19 November 1994:

Q: (T) I have not been remembering most of my dreams.

A: Try melatonin; avoid any antidepressants. Some have suggested.

Session 9 June 1996:

Q: (L) Well, apparently a lot of people who have psychotic episodes, literally go out of their minds. They can no longer function in this world. They LOCK them up!

A: Yes...

Q: (L) Why does melatonin induce these openings?

A: Gentle hallucinogen.

Q: (L) SV's mother took it and got all discombobulated with it!

A: Perception is key. If you really "dig" 3rd density, it makes you uncomfortable to see into the higher densities.

Q: (L) Can one use something like this and grow accustomed to the higher densities?

A: Ask Timothy Leary.

Q: (S) It's too late now! He's in 5 D! (L) Ask him for us.

A: We did, and he liked it a lot!

Q: (L) Did all of his use of hallucinogenics make it easier for him to transition?

A: Yes.

Q: (L) Where is he now?

A: 5th density.

Session 23 October 1999:

Q: I want to you have lost a fan because he was not happy with what he considered to be "internal inconsistencies" in that you were NOT favorably disposed toward hallucinations produced by substances such as Mescaline and Ayahuasca, but yet you recommend Melatonin because it is a hallucinogen. Then, you said that spiritual powers could not be obtained through chemicals or plant type means, but then said that Melatonin exercises psychic abilities. Could you comment on this?

A: Several comments: First of all, "fan" is short for "fanatic." Secondly, melatonin does not force an alteration in physiological brain chemicals, as do mescaline, peyote, LSD, etc. Accessing the higher levels of psychical awareness through such processes is harmful to the balance levels of the prime chakra. This is because it alters the natural rhythms of psychic development by causing reliance on the part of the subject, thus subjugating the learning process. It is a form of self-imposed abridging of free will. Melatonin simply allows the system to clear obstructions in the brain chemistry naturally, thereby allowing the subject to continue to learn at a natural pace. And, it is by no means unimportant that melatonin is a natural body hormone. The other substances mentioned are, at least in part, synthetic, with the exception of peyote. But even that is not a natural ingredient of the human physiological being. And besides, we have already discussed the importance, or lack thereof, of those who pass judgment upon this exercise, or communication.

Just in case some are having different reactions to melatonin it might help to realize it may affect some in different ways to different degrees depending on genetics etc..

 

[Kay Kim]

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

 

[Agron]

A: Ask Timothy Leary.

Q: (S) It's too late now! He's in 5 D! (L) Ask him for us.

A: We did, and he liked it a lot!

Q: (L) Did all of his use of hallucinogenics make it easier for him to transition?

A: Yes.

Q: (L) Where is he now?

A: 5th density.

Glad to hear that! Thanks for posting @goyacobol


Awesome info on melatonin in this thread too!! Thanks all
Started with it recently and I have good results. 3mg one hour before sleep.
Whats funny I had the need for it and had it at home (as a backup) but didnt remember to use it untill Ive seen it in "The Wave" series. Go figure..
Thanks a million Laura and Cs!!