Blog homepage: http://lysanderdusseljee.blogspot.com/

This paper as as commentable google doc.

This paper as a published google doc.

Prelude

Some of these notes were taken years ago, so do not have optimal or even consistent formatting. I’ll give it an overhaul if I have time. Certain notes may be out of context to readers, so may not make sense. Since sleep is my primary problem, most of it is intended to be in the context of improving sleep. Another problem is that, since these links were intended for myself, I didn’t make notes regarding topics I know well and thus consider obvious. Not all sources linked are reputable, and are intended only to remind myself to look into it further, as well as give me a place to start researching. Some content is copied from emails/forums/etc. that I wrote.

Table of contents

ANS (autonomic nervous system)

Hypotension

Blood volume

Albumin [note: I haven't yet moved links already under “blood volume” to this section]

Erythropoietin / red blood cells (RBC)

Pregnancy

Specific drugs.

Nicotine

Menthol

Methylxanthines (e.g. caffeine and theobromine)

Caffeine only

Includes theobromine

Theophylline increases thyroid (theobromine should work), should counteract the Wolff–Chaikoff effect

Tianeptine

Naltrexone

L-dopa (levodopa)

MK-677 ()

B3 (nicotinic acid; niacin; flushing form)

Sleep

Summaries of the only human trial of nicotinamide for sleep

Macronutrient metabolism and HGH

Other

Neurotransmitters and/or brain systems.

Acetylcholine

Histamine

Hydroxyzine

Atypical sedating Antipsychotics, 5-HT2A (serotonin 2A) antagonism, dopamine etc.

Disease states and organs.

CFS (chronic fatigue syndrome)

POTS (postural orthostatic tachycardia syndrome) and orthostatic hypotension

Thyroid

Thyroid and Chronobiology

Thyroid and Body Temperature

Cancer

Leukemia, myeloma, and lymphoma (blood cancers)

Chronic lymphoid leukemia (CLL)/B-cell chronic lymphocytic leukemia (B-CLL)

cGMP and cancer (exclusionary catchall)

IGF-1 and cancer

Curcumin

Excitotoxicity

Inflammation’s role in excitotoxicity.

Diet

Long chain saturated fat induced insulin resistance (LCSFAs, ceramides, IMTG, DAG, etc)

Ketosis

MCT oil

Intermittent fasting.

Miscellaneous and/or not yet fully categorized.

Avoiding tolerance/reverse tolerance

MDMA reverse tolerance

Opiate/opioid reverse tolerance

Macro-nutrients, Keto/high-carb, calories, insulin, diabetes, etc.

muscle + exercise

Protein and Muscle (an excerpt from an incomplete blog post I was writing)

antioxidants and oxidative stress

sleep drugs and biochemistry

cAMP, cGMP (cyclic AMP/GMP) and phosphodiesterase

bbb (blood-brain barrier)

for later research and/or oddities.

sleep posture

ANS (autonomic nervous system)

Notably, heart-rate variability [as a measure of parasympathetic nervous system activation] during sleep explained much of the variance in post-nap performance improvement on the creativity tasks: while sleep variables alone accounted for 46 percent of the variance in performance improvement on primed questions, sleep variables plus heart-rate variability accounted for 73 percent of the variance. Including heart-rate variability boosted the variance explained for repeated RAT questions from 26 percent to 58 percent.

http://www.the-scientist.com/?articles.view/articleNo/46305/title/Examining-Sleep-s-Roles-in-Memory-and-Learning/

http://www.pnas.org/content/113/26/7272.abstract

Baroreflex control of sympathetic nerve activity and heart rate in obstructive sleep apnea. [phenylephrine]

https://www.ncbi.nlm.nih.gov/pubmed/9856970

To dip or not to dip: on the physiology of blood pressure decrease during nocturnal sleep in healthy humans. [phenylephrine]

https://www.ncbi.nlm.nih.gov/pubmed/17353512

The pressor hyperresponsiveness to phenylephrine unmasks sympathetic hypofunction in migraine.

https://www.ncbi.nlm.nih.gov/pubmed/2611881

Impact of phenylephrine administration on cerebral tissue oxygen saturation and blood volume is modulated by carbon dioxide in anaesthetized patients

https://academic.oup.com/bja/article/108/5/815/267089/Impact-of-phenylephrine-administration-on-cerebral

Effects of selective slow-wave sleep deprivation on nocturnal blood pressure dipping and daytime blood pressure regulation

Moreover, daytime resting and ambulatory BP and HR were not altered, and morning MSNA and HRV did not differ significantly, indicating that baroreflex-mediated sympathoneural BP regulation was not affected by the preceding SWS deprivation.

http://ajpregu.physiology.org/content/298/1/R191

Hypotension

Sleep-disordered breathing and hypotension.

http://www.ncbi.nlm.nih.gov/pubmed/11673217

Control of cerebral blood flow during sleep and the effects of hypoxia.

http://www.ncbi.nlm.nih.gov/pubmed/17089880

Association of low blood pressure with anxiety and depression: the Nord‐Trøndelag Health Study

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2465598/

Sesamol ameliorates hypotension by modulating cytokines and PPAR-gamma in systemic inflammatory response

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732502/

[a blog post I wrote]  Low Blood Pressure (Hypotension), Sodium/Salt, and Sleep.

http://lysanderdusseljee.blogspot.com/2016/05/low-blood-pressure-hypotension.html

Blood volume

Albumin injection improves sleep in rats.

http://europepmc.org/abstract/MED/9748091

Phosphodiesterase 4 inhibition attenuates atrial natriuretic peptide-induced vascular hyperpermeability and loss of plasma volume.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3043537/

Oxidant-increased endothelial permeability: prevention with phosphodiesterase inhibition vs. cAMP production.

http://www.ncbi.nlm.nih.gov/pubmed/10710376

Effects of cilostazol, a phosphodiesterase inhibitor [PDE2/cAMP specific], on urinary excretion of albumin and prostaglandins in non-insulin-dependent diabetic patients.

http://www.sciencedirect.com/science/article/pii/016882279390132O

Chronic vasodilation produces plasma volume expansion and hemodilution in rats: consequences of decreased effective arterial blood volume

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023232/

Importance of post-exercise hypotension in plasma volume restoration. [Humans]

http://www.ncbi.nlm.nih.gov/pubmed/10848641

Effects of Long-term Nitric Oxide Synthesis Inhibition on Plasma Volume Expansion [reduced. I.e. NO may be needed for blood volume expansion] and Fetal Growth in the Pregnant Rat

http://hyper.ahajournals.org/content/26/6/1019.long

Nitric oxide synthase blockade and body fluid volumes [decreases plasma, increases extracellular (i.e interstitial/tissue fluid expansion) and total fluid]

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2002000100019

Dual Role for Nitric Oxide in the Regulation of Plasma Volume and Albumin Escape During Endotoxin Shock in Conscious Rats

inhibition of cNOS potentiates, whereas inhibition of iNOS markedly attenuates, losses in plasma volume and albumin escape elicited by LPS [lipopolysaccharide]

http://circres.ahajournals.org/content/81/5/840.full

The main cardiovascular changes in anaphylaxis are fluid extravasation and vasodilation, which result in a mixed distributive-hypovolemic shock pattern. The increased vascular permeability in anaphylaxis can result in transfer of 50% of intravascular fluid into the extravascular space within 10 minutes.

http://www.medscape.com/viewarticle/554567_3

The sympathetic nervous system and blood volume regulation: lessons from autonomic failure patients.

https://www.ncbi.nlm.nih.gov/pubmed/17630595

Role of the Sympathetic Nervous System in Regulating Renin and Aldosterone Production in Man [increases sodium retention]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC442043/

Even during and after the first training session, cortisol secretion from the adrenal cortex is elevated, which stimulates hepatic production of albumin

https://www.ncbi.nlm.nih.gov/books/NBK54474/

Morphine sulfate attenuates hemorrhagic shock-induced hyperpermeability.

These results suggest that instead of aggravating the inflammatory response after hemorrhagic shock, morphine may provide protection to the microvasculature.

https://www.ncbi.nlm.nih.gov/pubmed/16790645

Despite these vascular effects, morphine is usually not accompanied by a significant change in cardiac output, except in patients who are hypovolemic or in an upright posture. Although other opioids by themselves rarely cause hypotension, all opioids may cause hypotension when used in combination with other sedative drugs, especially propofol or benzodiazepines. This effect is exaggerated in hypovolemic patients.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227310/

Expansion of the CBV by alpha-blocker therapy was related to lower blood pressures after resection of the pheochromocytoma.

https://www.ncbi.nlm.nih.gov/pubmed/15010400

Long term use of midodrine is not recommended due to chronic activation of the sympathetic nervous system which can reduce blood volume

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390096/

Interstitial fluid pressure, composition of interstitium, and interstitial exclusion of albumin in hypothyroid rats.

https://www.ncbi.nlm.nih.gov/pubmed/10775143

"sometimes athlete’s hematocrit levels will drop lower, to levels that are flagged as “low” and the athlete can be told he has anemia, even when he does not.  In some studies,  the relationship between hematocrit and  fitness is an inverse one, meaning that athletes with the lowest hematocrit were actually the fittest athletes in the study."

This suggests that changes in plasma are generally more significant than that of red blood cells.

Regulation of plasma volume during obstructive sleep apnoea.

http://www.ncbi.nlm.nih.gov/pubmed/10607185

Circulatory volume in essential hypertension. Relationships with age, blood pressure, exchangeable sodium, renin, aldosterone and catecholamines.

These observations do not support the concept that hypervolemia may represent the initial event leading to high blood pressure in essential hypertension; in contrast, changes in blood volume appear to reflect variations in blood pressure.

https://www.ncbi.nlm.nih.gov/pubmed/6387428

Acute hypervolemia, cardiac performance, and aerobic power during exercise.

Arterial blood pressures were either unchanged or lowered.

https://www.ncbi.nlm.nih.gov/pubmed/7096143

Vasopressin increases urinary albumin excretion in rats and humans: involvement of V2 receptors and the renin-angiotensin system

http://www.ncbi.nlm.nih.gov/pubmed/12584270

Vasopressin Inhibits Type-I Collagen and Albumin Gene Expression in Primary Cultures of Adult Rat Hepatocytes

http://www.jbc.org/content/624/16/9583.full.pdf

Effect of lymphatic outflow pressure on lymphatic albumin transport in humans.

Thus posture-dependent changes in lymphatic protein transport are modulated by changes in CVP [Central Venous Pressure] through its mechanical impact on lymphatic outflow pressure.

https://www.ncbi.nlm.nih.gov/pubmed/11509519

Norepinephrine-induced vasoconstriction results in decreased blood volume in dialysis patients

http://ndt.oxfordjournals.org/content/21/5/1305.full

Effect of glucagon on cyclic AMP, albumin metabolism and incorporation of 14C-leucine into proteins in isolated parenchymal rat liver cells.

https://www.ncbi.nlm.nih.gov/pubmed/184684

Relation of Plasma to Interstitial Fluid Volume in Essential Hypertension

This could not be explained only on the basis of the diminished plasma volume found in hypertensive patients . . . Peripheral plasma renin activity correlated inversely with plasma volume, but not with extracellular water volume, suggesting that these two indices of body fluid volume are not always functionally inter- changeable.

http://circ.ahajournals.org/content/circulationaha/40/3/357.full.pdf

The release mechanism for atrial natriuretic factor during blood volume expansion and tachycardia in dogs.

We conclude that atrial tension or stress, developing during each atrial systole, is an important determinant of ANF release. Since atrial diastolic and systolic dimensions do not increase during pacing tachycardia, ANF release is not dependent on atrial distension.

https://www.ncbi.nlm.nih.gov/pubmed/2976238

The influence of intravascular volume expansion on cerebral blood flow and blood volume in normal rats.

In normal brain, CBF does not change during volume expansion

https://www.ncbi.nlm.nih.gov/pubmed/8489067

Human cardiovascular variability, baroreflex and hormonal adaptations to a blood donation.

https://www.ncbi.nlm.nih.gov/pubmed/9730845

PLASMA VOLUME AND EXTRACELLULAR FLUID VOLUME DURING LONG-TERM TREATMENT WITH PROPRANOLOL IN ESSENTIAL HYPERTENSION

http://sci-hub.cc/10.1042/cs0430165

Albumin [note: I haven't yet moved links already under “blood volume” to this section]

The role of albumin in critical illness

https://academic.oup.com/bja/article/85/4/599/272431/The-role-of-albumin-in-critical-illness

The Stimulation of Albumin Synthesis by Methadone

http://www.gastrojournal.org/article/S0016-5085(76)80190-4/abstract

Stimulation of human albumin synthesis and gene expression by growth hormone treatment

Conclusion: These results suggest that GH may induce a quick, gene expression-independent increase in albumin synthesis, which is sustained by a later-occurring increase in albumin gene expression.

http://www.sciencedirect.com/science/article/pii/S0261561400901584

High protein diets stimulate albumin synthesis at the site of albumin mRNA transcription.

[note that it could be due to protein frequency rather the actual protein itself, which is roughly my current stance on protein for muscle.]

https://www.ncbi.nlm.nih.gov/pubmed/2561516

Effect of silymarin in diabetes mellitus patients with liver diseases

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198528/

The percentage increase in the albumin levels with silymarin treatment was 16.01 ± 15.06% and with l-ornithine + l-aspartate was 25.39 ± 15.16%

Hepatoprotective effect of silymarin

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959115/

It has also been shown that silymarin increases protein synthesis in hepatocytes by stimulating RNA polymerase I activity.

Erythropoietin / red blood cells (RBC)

Triggering of erythropoietin production by hypoxia is inhibited by respiratory and metabolic acidosis

https://core.ac.uk/download/pdf/11555049.pdf

Acute blood loss causes respiratory alkalosis that was associated with an increase in erythropoietin, both of which normalized after 24 hours.

The effects of acute bleeding on acid-base balance erythropoietin (Ep) production and in vivo P50 in the rat.

https://www.ncbi.nlm.nih.gov/pubmed/1276082

Effects of Theophylline on Erythropoietin Production in Normal Subjects and in Patients with Erythrocytosis after Renal Transplantation

http://www.nejm.org/doi/full/10.1056/NEJM199007123230203#t=article

[Some random notes I found, for use as research starting points]

http://www.ld99.com/reference/old/text/2878909-467.html

Pregnancy

Heart rate, blood volume, and cardiac output increase during pregnancy.

Figure 3

http://cardiovascres.oxfordjournals.org/content/101/4/545

Despite the increased blood volume, sleep is impaired. I think that this is likely related the elevated heart rate (due to increased cardiac demand/output). http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2010.181.1_MeetingAbstracts.A6529

Specific drugs.

Nicotine

dose dependent sleep enhancement rats (REM)

http://www.ncbi.nlm.nih.gov/pubmed/10463313

http://science.utep.edu/bridges/index.php/are-nicotinic-receptors-involved-in-regulating-rem-sleep-architecture-of-the-rat

(REM)

Enhance rem in depressed patients

Acute.

http://www.ncbi.nlm.nih.gov/pubmed/11995405 (REM)

Chronic

http://www.ncbi.nlm.nih.gov/pubmed/15631874 (Mostly SWS)

4 nights

http://www.ncbi.nlm.nih.gov/pubmed/9592048 (REM)

Dose dependent sleep enhancement in man

http://www.ncbi.nlm.nih.gov/pubmed/24687640

http://www.ncbi.nlm.nih.gov/pubmed/7962682

low dose nicotine during development enhances learning while high dose impair learning in rats. (mechanism counteracting stress?)

http://www.scienceagogo.com/news/20031012195753data_trunc_sys.shtml

ANS in memory from sleep.

http://www.the-scientist.com/?articles.view/articleNo/46305/title/Examining-Sleep-s-Roles-in-Memory-and-Learning/

oral nicotine up to 18mg

http://onlinelibrary.wiley.com/doi/10.1002/ibd.3780111209/abstract

"The oral bioavailability of nicotine is about 20 to 45% (Benowitz et al., 1991; Compton et al., 1997; Zins et al., 1997)."

http://pharmrev.aspetjournals.org/content/57/1/79.full

Effects of nicotine [6+ mg/kg; may be irrelevant due to dose] on heart dimensions and blood volume in male and female rats.

Nicotine reduced heart weight, heart length, and overall blood volume.

https://www.ncbi.nlm.nih.gov/pubmed/12791529

Effects of Nicotine on Cardiovascular Remodeling in a Mouse Model of Systemic Hypertension

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070620/

"Histopathological analysis of aortas revealed that mice receiving combined nicotine and Ang II treatment induced significant hypertrophy compared to all other groups."

"Nicotine was delivered at a target rate of 5 mg/kg/day, and Ang II was delivered at 21.6 µg/d, calculated based on initial weight and assumed weight gain of 0.5 g per week (normal chow diet), for a total of 4 weeks."

"It is important to note that the dosage used in the present study is likely high compared to the typical high initial dose of nicotine in a patch form (20–25 mg/day in a 70 kg subject). However, the mouse metabolism of nicotine is notoriously high (27) and the mice also insensitive to many of the neurobehavioral effects of nicotine, and thus we predict that the level used for the present study is a reasonable starting point for assessing potential adverse cardiovascular effects."

Characterization of tobacco withdrawal: physiological and subjective effects.

https://www.ncbi.nlm.nih.gov/pubmed/3934546

Thus, objective data indicate that after tobacco deprivation smokers actually sleep longer, which contradicts subjective reports of insomnia.

Characterization of tobacco withdrawal: physiological and subjective effects.

https://www.ncbi.nlm.nih.gov/pubmed/3934546

Thus, objective data indicate that after tobacco deprivation smokers actually sleep longer, which contradicts subjective reports of insomnia.

Menthol

analgesia, antiexcitatory, anti inflammatory-pain.

http://www.ncbi.nlm.nih.gov/pubmed/22951274

Kappa-opioid agonism by menthol.

http://www.ncbi.nlm.nih.gov/pubmed/11897159

100mg/kg injection calcium channel blocking.

http://jpet.aspetjournals.org/content/343/3/661.long

Menthol GABA(A) agonist.

journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0003386

Menthol enhances phasic and tonic GABAA receptor-mediated currents in midbrain periaqueductal grey neurons

http://onlinelibrary.wiley.com/doi/10.1111/bph.12602/full

menthol lowers blood pressure via TRPM8

http://hyper.ahajournals.org/content/63/6/1354.full

Disposition kinetics and effects of menthol.

Menthol reduced subjective vigor value at 30 minutes.
https://www.ncbi.nlm.nih.gov/pubmed/10460066

Methylxanthines (e.g. caffeine and theobromine)

Caffeine only

caffeine tolerance enhance SWS in rats

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762801/

Caffeine half life in insomniacs (max 11.4 hours).

http://www.holisticprimarycare.net/topics/topics-o-z/vitamins-a-supplements/1246-nutritional-treatments-for-insomnia.html

partial tolerance to caffeine induced cortisol response in healthy adults in 5 days.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2257922/

Caffeine alone induced a significant increase in blood pressure associated with a decrease in heart rate,

The cardiovascular interaction between caffeine and nicotine in humans.

https://www.ncbi.nlm.nih.gov/pubmed/8354027

Caffeine affects cardiovascular and neuroendocrine activation at work and home.

Caffeine administration significantly raised average ambulatory blood pressure during the workday and evening by 4/3 mm Hg and reduced average heart rate by 2 bpm.

https://www.ncbi.nlm.nih.gov/pubmed/12140349

The Effect of Daily Caffeine Use on Cerebral Blood Flow: How Much Caffeine Can We Tolerate?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748160/

Includes theobromine

the absolute bioavailability of theobromine approached 100% . [. . .]

The ratio of brain:blood theobromine concentrations decreased continuously from 0.96 at birth to 0.60 in 30-day-old rats. After 24 hr, no organ accumulation of theobromine or its metabolites could be seen in adult animals. [rabbits]

https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+7332

The influence of caffeine and theobromine on locomotive activity and the brain cGMP/cAMP ratio in white mice.

[Despite being a phosphodiesterase (PDE) inhibitor, caffeine actually lowered brain cAMP. Theobromine prevented caffeine's lowering effect, but had no effect on it's own]

http://sci-hub.cc/10.1016/0006-2952%2877%2990152-6

theophilline (1,3-dimethylxanthine) and theobromine, more effective PDE inhibitors [than caffeine], were characterized

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195739/

At 50% inhibition, theophylline was 6.7- and 5.8 fold more potent than theobromine and caffeine, respectively.

http://www.jbc.org/content/237/4/1244.long

Theobromine has two- and threefold lower affinity than caffeine for the A1 and A2A receptors

Psychopharmacology of theobromine in healthy volunteers

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672386/

xanthine derivatives (for example, theophylline and caffeine), which inhibit almost all PDE families (except for PDE8 and PDE9)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155750/

Caffeine inhibits forskolin-stimulated cyclic AMP accumulation in rat brain. [and so does, to a lesser extent, theobromine]

http://www.sciencedirect.com.sci-hub.cc/science/article/pii/001429999090231T

Theobromine up-regulates cerebral brain-derived neurotrophic factor [bdnf] and facilitates motor learning in mice.

https://www.ncbi.nlm.nih.gov/pubmed/27833051

Theophylline increases thyroid (theobromine should work), should counteract the Wolff–Chaikoff effect

Theophylline increases the uptake of radioiodine by mouse thyroid.

https://www.ncbi.nlm.nih.gov/pubmed/15483348

[Effect of theophylline on the thyroid function in healthy subjects: comparison between the short- and long-term medication].

https://www.ncbi.nlm.nih.gov/pubmed/8295345

Effect of sustained-release theophylline administration on pituitary-thyroid axis.

These results indicate that the therapeutic doses of theophylline significantly but transiently increased the serum T4 level. In most cases, T4 is metabolized to rT3, an inactive metabolite of T4, but in a few cases it is metabolized to T3, which might double the side effects of theophylline.

https://www.ncbi.nlm.nih.gov/pubmed/6292280

Modulation of thyroidal radioiodine uptake by theophylline

[reduced radioiodine in thyroid in humans when radioiodine was administered on 4th (5th?) day of theophlline. Increased thyroid hormone production was suggested as one possible mechanism for this, thus being released from and therefore not found in the thyroid]

[also noted dose dependence in vitro, where higher concentration do not increase uptake but low concentrations do]

http://www.sciencedirect.com/science/article/pii/S0014480004000437

Graves’ Disease and the Manifestations of Thyrotoxicosis

“The thyroid uptake of 131I is acutely depressed in thyrotoxic patients by administration of 2 mg potassium iodide, whereas more than 5 mg is needed to depress uptake in normal subjects. Concentrations of serum iodide above 5 µg/dl block binding in the thyrotoxic gland [216-219].

The biochemical mechanism of the Wolff-Chaikoff block is not clear. Iodide does not prevent TSH or TSAb binding to the TSH membrane receptor, but does inhibit both TSH-stimulated adenyl cyclase production of cAMP, and cAMP actions”

“Coincident with the block in uptake, iodide also causes a marked reduction in the release of previously formed hormone from the thyrotoxic gland. This phenomenon has been repeatedly observed and helps to explain the beneficial therapeutic effect of iodide in Graves”

https://www.ncbi.nlm.nih.gov/books/NBK285567/

Tianeptine

I was buying some supplements on this site, when I came across this antidepressant with analgesic properties. The mechanism eluded is glutamate receptor antagonism. The therapeutic dose for depression is ~15mg, so it is pretty potent. Here is a quote from one of the reviews:

"at doses of 60mg the pain killing effects are better and far less addicting then any opiate. this has become the stple for my breakthrough pain relief. i suffer from multiple spine problems and a metal rod in my leg."

5g powder is ~30 bucks: enough for ~80 painkilling doses. By rotating it and/or combining it with other drugs, tolerance can be mitigated.

http://www.powdercity.com/products/tianeptine-powder

Some of this may be mediated by opioid agonism. In particular mu-opioid agonism, but, to a lesser extent, also delta-opioid agonism.

http://www.nature.com/tp/journal/v4/n7/full/tp201430a.html

It appears quite clear that tianeptine can be abused, but this seems quite rare relative to the number of people using it therapeutically (and successfully, I might add). This only appears to happen in very irresponsible people.

This study mentions inflammatory pain, specifically mentioning "serotonergic and adrenergic transmission at the spinal level".

http://www.ncbi.nlm.nih.gov/pubmed/22253265

This study on thermal analgesia also mentions serotonergic activity.

http://www.ncbi.nlm.nih.gov/pubmed/10227587

And this study says tianeptine modulated glutamatergic tone. Seeing as glutamate is the chief excitatory neurotransmitter in the CNS, one would expect glutamatergic modulation to reduce hyperexcitation in a similar way to gabaergic mechanisms.

"Specifically, acute restraint stress increases extracellular levels of glutamate in the BLA as measured by in vivo microdialysis, an effect that was inhibited by tianeptine."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902200/

And indeed, while I saw a human observational study showing no effect, this rat study indicates anti-epileptic effects. It suggests that this effect may be adenosine receptor mediated.

http://www.ncbi.nlm.nih.gov/pubmed/16823386

This study implicates the same receptor in antinociception.

http://www.ncbi.nlm.nih.gov/pubmed/3017496

Note, however, that caffeine, an adenosine antagonist, both develops and loses tolerance very rapidly; on the order of days/weeks."complete tolerance was observed after consumption of 300 mg taken 3 times a day for 18 days".[wiki] The good aspect of that is that stopping the drug for a week or so should eliminate nearly all tolerance. Specifically, caffeine withdrawal can last "2-9 days".

https://www.ncbi.nlm.nih.gov/pubmed/15448977

The side effects of tianeptine sound minimal and uncommon.

"The most common adverse effects are nausea, constipation, abdominal pain, headache, dizziness and changes in dreaming. Anticholinergic effects occur less often with tianeptine than with tricyclic agents. Hepatoxicity is rare. The dosage should be decreased in elderly patients and those with severe renal failure, but adjustment is not necessary in patients with alcoholism or hepatic impairment, or those undergoing haemodialysis."

http://www.ncbi.nlm.nih.gov/pubmed/11463130

Since I get the impression that tianeptine is a dirty drug (i.e. has multiple mechanisms of action), it's propensity to cause side effects should be reduced. Single target drugs have a greater chance of overwhelming a specific system. However, this does raise the chances of drug interaction.

Naltrexone

Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats.

Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence.

https://www.ncbi.nlm.nih.gov/pubmed/11805221

L-dopa (levodopa)

Effect of L-dopa in young patients with hypertension.

In response to L-dopa, 250 mg administered orally, the blood pressure decreased significantly as compared with the results of placebo treatment. … These results suggest that the blood pressure-lowering effect of L-dopa may be mediated through multiple sites involving D1 dopamine receptors, the central nervous system, and the renin-angiotensin system.

https://www.ncbi.nlm.nih.gov/pubmed/1928809

MK-677 ()

Effectively no clear change in blood pressure or heart rate in otherwise healthy obese subjects with low heart rate (~60bpm and ~80dbp).
http://press.endocrine.org/doi/full/10.1210/jcem.83.2.4539

Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man.

https://www.ncbi.nlm.nih.gov/pubmed/9349662

B3 (nicotinic acid; niacin; flushing form)

Sleep

https://www.ncbi.nlm.nih.gov/pubmed/1809857

http://sci-hub.cc/10.1016/0306-9877(91)90012-n

Sleep deprivation-induced dermatitis: further support of nicotinic acid depletion in sleep deprivation.

[full abstract] It is noted that some of the manifestations of prolonged sleep deprivation are similar to changes seen in pellagra. Dermatitis is one of the cardinal clinical manifestations of human pellagra. Prolonged sleep deprivation also typically induces a dermatitis in experimental animals. Both dermatidities are histopathologically similar. It is plausible that both may have a similar etiology, i.e. depletion of nicotonic acid and products derived from it.

[they specify acral dermatitis, “Acral distribution of a dermatosis means it affects distal portions of limbs (hand, foot) and head (ears, nose).”(wiki)]

https://www.ncbi.nlm.nih.gov/pubmed/2062264

http://sci-hub.cc/10.1016/0306-9877(91)90224-m

Sleep Deprivation-Induced Neuronal Damage may be

Due to Nicotinic Acid Depletion

[full abstract] Prolonged sleep deprivation induces chromatolysis of central nervous system

neurons. This unusual form of neuronal damage is curiously similar to the neuronal damage

seen in pellagra. It is proposed that the neuronal damage of prolonged sleep deprivation is a

consequence of nicotinic acid depletion.

Summaries of the only human trial of b3 (nicotinamide, non-flush form) for sleep

https://www.researchgate.net/publication/22946570_The_effects_of_nicotinamide_upon_sleep_in_humans

“Abstract To study the effects of nicotinamide on the sleep process in man, 6 subjects with normal sleep patterns and 2 subjects with moderate to severe insomnia were chosen. For all subjects with normal sleep patterns there was a significant increase in REM sleep at the 0.002 confidence level, using base line and recovery as control data, and after 2 and 3 wk as experimental data. The changes in all other stages of sleep were not significant. In preliminary studies using 2 female subjects with moderate to severe insomnia, it appeared that the nicotinamide did not improve sleep within 2 wk; but by the 3rd wk of drug ingestion, there were significant results. Again, using base line and recovery data as control, REM sleep was significantly increased after the 3rd wk at the 0.001 confidence level.”

Diet promotes sleep duration and quality

https://www.researchgate.net/publication/225087663_Diet_promotes_sleep_duration_and_quality

Administration of nicotinamide(niacin) to 6 people with normal sleep pattern increased REM sleep, and when given to subjects with moderate to severe insomnia, the sleep efficacy, recorded in a sleep laboratory using electroencephalogram, was improved [68]. Niacin is biosynthesized from dietary TRP via the so-called kynurenine pathway. The researchers speculate that administration of niacin results in the buildup of nicotinamide adenine dinucleotide, which may reduce the amount of TRP converted to niacin, thus leaving TRP available to the synthesis of serotonin and melatonin.

http://www.aasmnet.org/jcsm/ViewAbstract.aspx?pid=26314

Oral Nonprescription Treatment for Insomnia: An Evaluation of Products With Limited Evidence [nicotinamide (flush-free form)]

Nicotinamide (Niacin) [non-flush form] is biosynthesized from dietary tryptophan via the kynurenine pathway and quinolinic acid. In six normal patients given escalating doses of nicotinamide for two days followed by 3 g daily for 21 days, significant (P = .002) increases in REM sleep were measured (18.4% baseline vs 25.0% at the end of treatment).142 Using the same protocol, two female patients with insomnia experienced an increase in sleep efficiency from 58.5% at baseline to 79.5% after three weeks, with a return to 41.5% after cessation of nicotinamide.142

Macronutrient metabolism and HGH

http://ajpendo.physiology.org/content/279/1/E50

Effects of nicotinic acid on fatty acid kinetics, fuel selection, and pathways of glucose production in women

“We conclude that chronic effects of NA on FFA metabolism are complex (acute suppression followed by overshoot of Ra FFA and [FFA] on top of a trend toward basal elevations), that responses after NA are consistent with operation of a glucose-fatty acid cycle in peripheral tissues, and that secondary effects on EGP were through changes in glycogenolysis, not gluconeogenesis.”

The growth hormone response to repeated bouts of sprint exercise with and without suppression of lipolysis in men

http://jap.physiology.org/content/104/3/724

“participants ingested NA (1 g 60 min before, and 0.5 g 60 and 180 min after sprint 1)”

"A single 30-s sprint is a potent physiological stimulus for growth hormone (GH) release. However, repeated bouts of sprinting attenuate the GH response, possibly due to negative feedback via elevated systemic free fatty acids (FFA)."

"Peak and integrated GH were significantly greater following sprint 2 compared with sprint 1 in the NA trial [peak GH: 23.3 (7.0) vs. 7.7 (11.9) μg/l, P < 0.05; integrated GH: 1,076 (350) vs. 316 (527) μg·l−1·60 min−1, P < 0.05]"

Other

Ocular Effects of Niacin: A Review of the Literature

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458328/#__sec5title

Many authors reported ocular side effect after therapy with niacin. Fraunfelder et al. (5) reported that 3 g or more per day of nicotinic acid, could cause blurred vision, eyelid edema, toxic amblyopia, proptosis, loss of eyelashes or eyebrow, superficial punctate keratitis and CME. Some cases of blurred vision were reported in the literature (73), and 18 cases were reported to the National Registry or the FDA spontaneous reporting system. In these cases, the average dose of niacin was 1.5–2 g per day, with a duration of therapy varying from 6 weeks to 1 year. Follow-up reported complete resolution of visual symptoms after discontinuing niacin. Dry eye was explained because this vitamin may be secreted and concentrated in human tears, thereby irritating an already dry eye.

Neurotransmitters and/or brain systems.

Acetylcholine

Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC357065/

Slow-wave sleep, acetylcholine, and memory consolidation

http://www.pnas.org/content/101/7/1795.full

“Treatment with the acetylcholine esterase inhibitor physostigmine, however, selectively blocked the performance improvement in the declarative memory task normally observed after sleep.”

Differential effects of scopolamine on nocturnal cortisol secretion, sleep architecture, and REM latency in normal volunteers: relation to sleep and cortisol abnormalities in depression.

https://www.ncbi.nlm.nih.gov/pubmed/2930809

[acetylcholine is normally considered a vasodilator. I’m posting this study because the intricacies of drugs are rarely captured, thus many are confused regarding paradoxical effects, though this effect of acetylcholine may be mute in practice]

Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries.

Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). By contrast, if the endothelium is removed experimentally, acetylcholine constricts blood vessels.

https://www.ncbi.nlm.nih.gov/pubmed/3093861

Histamine

HISTAMINE IN THE REGULATION OF WAKEFULNESS

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016451/

An adenosine A2A receptor agonist induces sleep by increasing GABA release in the tuberomammillary nucleus to inhibit histaminergic systems in rats

http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2004.02991.x/pdf

Caffeine promotes glutamate and histamine release in the posterior hypothalamus.

https://www.ncbi.nlm.nih.gov/pubmed/25031227

Induction of prolonged, continuous slow-wave sleep by blocking cerebral H₁ histamine receptors in rats.

https://www.ncbi.nlm.nih.gov/pubmed/21699505

Therapeutic rationale for low dose doxepin in insomnia patients

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027305/

Adenosine antagonizes the histamine-induced stimulation of human atrial myocardium: protection by H1-receptor blockade

http://vivo.med.cornell.edu/display/pubid0023077907

Hydroxyzine

Chloral hydrate versus hydroxyzine HCL for sedation prior to pediatric sleep EEG recording.

[hydroxyzine only 1mg/kg, from abstract. Hydroxyzine showed lower efficacy, likely do solely to dose]

https://www.ncbi.nlm.nih.gov/pubmed/23594140

Recent clinical trials of hydroxyzine in generalized anxiety disorder. [1998]

https://www.ncbi.nlm.nih.gov/pubmed/9777055

Comparing the effect of prazosin and hydroxyzine on sleep quality in patients suffering from posttraumatic stress disorder.

https://www.ncbi.nlm.nih.gov/pubmed/24993832

“Hydroxyzine dosage was started at 10 mg on the first evening

and continually increased over the first 10 days up to 100 mg, re-

maining thereafter at this level until the end of the study.”

Efficacy of the Sequential Administration of Melatonin, Hydroxyzine, and Chloral Hydrate for Recording Sleep EEGs in Children

http://eeg.sagepub.com/content/early/2015/12/31/1550059415621830?papetoc

Hydroxyzine: Rational choice for inpatients with insomnia

http://www.mdedge.com/currentpsychiatry/article/64228/sleep-medicine/hydroxyzine-rational-choice-inpatients-insomnia 

A pilot, open label, clinical trial using hydroxyzine in multiple sclerosis.

https://www.ncbi.nlm.nih.gov/pubmed/16388727 

Prevention of “learned helplessness” in the rat by hydroxyzine

http://onlinelibrary.wiley.com/doi/10.1002/ddr.430170306/abstract 

Atypical sedating Antipsychotics, 5-HT2A (serotonin 2A) antagonism, dopamine etc.

Atypical Antipsychotics: Sleep, Sedation, and Efficacy

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC487011/

Diazepam, promethazine and propiomazine as hypnotics in elderly inpatients.

https://www.ncbi.nlm.nih.gov/pubmed/6152029

Disease states and organs/systems.

CFS (chronic fatigue syndrome)

Adrenal fatigue does not exist: a systematic review.

[Most cases of so called “adrenal fatigue” are likely misdiagnosed chronic fatigue syndrome. However, while there is no reason to think the adrenal glands can be “worn out”, or any of that other nonsense, it is perfectly reasonable to suspect that high stress leads to chronic fatigue. I can think of several mechanisms by which this could occur. In contrast to adrenal fatigue, chronic fatigue definitely does exist. What’s more, chronic fatigue has some rather convincing mechanisms, whereas adrenal fatigue sounds like bullshit.]

https://www.ncbi.nlm.nih.gov/pubmed/27557747

Impaired blood pressure variability in chronic fatigue syndrome--a potential biomarker.

https://www.ncbi.nlm.nih.gov/pubmed/22670061

Elevated nocturnal [diastolic] blood pressure and heart rate in adolescent chronic fatigue syndrome.

http://www.ncbi.nlm.nih.gov/pubmed/21059182

Article that linked it.

http://www.healthrising.org/blog/2013/04/02/bad-sleep-poor-research-until-now-study-illuminates-the-cause-of-the-sleep-problems-in-chronic-fatigue-syndrome-finally/

Sleep-wake behavior in chronic fatigue syndrome.

We found no evidence of circadian rhythm disturbance in CFS. However, the role of autonomic activity in the experience of unrefreshing sleep warrants further assessment. The activity symptom-relationship modelled here is of clinical significance in the approach to activity and symptom management in the treatment of CFS”

https://www.ncbi.nlm.nih.gov/pubmed/21532961

30-50% blood volume reduction in CFS.

https://www.masscfids.org/more-resources-for-me-cfs/118-a-conceptual-breakthrough-dr-bell-relates-qvery-excitingq-new-findings-on-possible-causes-tests-treatments-for-cfids-symptoms?showall=&start=3

Electrocardiographic QT interval and cardiovascular reactivity in fibromyalgia differ from chronic fatigue syndrome.

https://www.ncbi.nlm.nih.gov/pubmed/18395162

POTS (postural orthostatic tachycardia syndrome) and orthostatic hypotension

Renin-Aldosterone Paradox and Perturbed Blood Volume Regulation Underlying Postural Tachycardia Syndrome

There was a paradoxically low level of aldosterone in the patients with POTS (190±140 pmol/L versus 380±230 pmol/L; P=0.017).

http://circ.ahajournals.org/content/111/13/1574

Effects of propranolol in a case of orthostatic hypotension.

In this patient, propranolol appears to normalise the response to the posture change, by restoring normal vasoconstriction in the upright position.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716342/#R8

Use of propranolol in the treatment of idiopathic orthostatic hypotension

Chronic oral administration of propranolol (40-160 mg/day) also elevated the blood pressures of these individuals with increases in the order of 20-35/15-25 mmg being observed.

https://www.ncbi.nlm.nih.gov/pubmed/611664

Thyroid

The thyroid hormone, parathyroid hormone and vitamin D associated hypertension

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230087/

Effects of Supraphysiological Doses of Levothyroxine on Sleep in Healthy Subjects: A Prospective Polysomnography Study

www.ncbi.nlm.nih.gov/pmc/articles/PMC3134320/

Free thyroxine concentrations in thyroid storm.

https://www.ncbi.nlm.nih.gov/pubmed/7212477

rT3 does NOT antagonise T3 receptors, though it does inhibit t4 to t3 conversion.

http://boards.straightdope.com/sdmb/showthread.php?t=702730

Decreased albumin levels are seen in patients with hypothyroidism, kidney disease, debilitating disease, burns, malnutrition, protein losing enteropathy, polydipsia, liver disease or anabolic hormone insufficiency.

http://www.babymed.com/laboratory-values/serum-albumin-during-pregnancy

"Cyclic AMP (cAMP) is the principal intracellular mediator of TSH effects in the thyroid, inducing both thyroid hormone production and cell proliferation." Conversely, thyroid stimulates cAMP in at least some tissues (e.g. adipose and kidneys). Of particular interest is that hypothyroidism reduces cAMP in the kidneys, where the kidneys are responsible for blood volume control not only by water/sodium excretion/retention, but also by erythropoietin production. Hyperthyroidism increases blood volume by both sodium reabsorbtion, and erythropoietin release, effects which I assume may be cAMP mediated.

Possibility of thyroid hormone resistance. Possibly just reduced t3: haven't researched enough, nor examined the referenced studies.
http://lesswrong.com/lw/nhs/the_thyroid_madness_two_apparently_contradictory/

"Low-dose liothyronine has been shown to improve depression symptoms in patients with normal thyroid function who do not have adequate relief from their depression after trying several different antidepressants. When added to existing medications, liothyronine helped achieve remission in 24% of patients participating in a subset of the large STAR*D depression trial.[3] According to a 2001 meta-analysis that analyzed the effectiveness of adding Liothyronine to tricyclic antidepressants, women in particular may benefit from Liothyronine.[4] The average effective dose for depression was 45 mcg of Liothyronine daily, which is lower than the doses used for treating hypothyroidism.[3] About 9% of patients stopped taking liothyronine due to side effects."

https://en.wikipedia.org/wiki/Liothyronine

Preventive Effect of Liothyronine on Electroconvulsive Therapy-Induced Memory Deficit in Patients with Major Depressive Disorder: A Double-Blind Controlled Clinical Trial

https://www.hindawi.com/journals/bmri/2015/503918/

TSH is Not the Answer: Rationale for a New Paradigm to Evaluate and Treat Hypothyroidism, Particularly Associated with Weight Loss

http://www.thyroidscience.com/hypotheses/rowsemitt.najarian.H.6.11/rowsemitt.najarian.6.11.pdf

Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC377492/

Thyroid hormones impact on sleep and other unconventional neuroproperties by Dr. Joseph V. Martin

http://joemartin.camden.rutgers.edu/papers/

Thyroid and Chronobiology

Effects of Thyroxine and Thyroparathyroidectomy on Circadian Wheel Running in Rats

[Severe hypothyroidism actually shortens free running circadian rhythm (actually a lot more complicated than that, based on other study discussions), while severe hyperthyroidism has no impact. However, hyperthyroidism reduced activity levels. The authors come up with what seems to me a bulshit explanation. I suspect this level of hyperthyroidism produces sleep disruption that could explain the reduced activity, and potentially all the impacts of both severe hyper and severe hypo thyroidism on free running rhythm. Chemically induced hypothyroidism generally lengthens free running period, possibly due to reduced severity compared to thyroidectomy. Thus, more moderate hyperthyroidism might be expected to reduce free running period. I thus still believe that mild {e.g. subclinical} hyperthyroidism could advance sleep phase.]

http://sci-hub.cc/http://www.sciencedirect.com/science/article/pii/009130579390348W

Effects of Hypothyroidism on Rat Circadian Activity and Temperature Rhythms and Their Response to Light

“On the other hand, thyroidectomized hamsters treated with the antithyroid drug thiourea have a
longer period of circadian wheel-running rhythms than controls under constant conditions
(Beasley and Nelson 1982). Similarly, treatment with the antithyroid drug propyithiouracil,
hypothyroidism lengthens the period of circadian wheel-running rhythms in freerunning
blinded hamsters and increases the phase-angle of wheel-running under LD (Morin
et al 1986). However, these results could not be replicated in hamsters made hypothyroid
using radioactive iodine (Morin 1988). Thus, species, gender, and choice of antithyroid
treatment may all contribute to the divergence of these results” [note: should look at degree of hypothyroidism in these studies mentioned]

http://sci-hub.cc/http://www.sciencedirect.com/science/article/pii/009130579390348W

Thyroid and Body Temperature

Hypothyroidism - new aspects of an old disease

The decrease in energy metabolism and heat production [in hypothyroidism] is reflected in the low basal metabolic rate, decreased appetite, cold intolerance, and slightly low basal body temperature.” I take the “slightly” to be important. I’ve heard several times that thyroid hormone is related to body temperature. I heard this (indirectly) when I saw a naturopath (last-ditch effort) and I was talking about how I wanted thyroid hormone, specifically T3, and my slightly high body temperature was mentioned. I’ve also seen this idea on several websites in the same vein. I was immediately sceptical, as I would expect that, under normal conditions, the thyroid primarily modulates peripheral temperature, as the primary control mechanism for core body temperature is via dissipation through the periphery. Additionally, thyroid hormone may play a role in temperature homeostasis (such as cold adaptation), but not likely in temperature determination.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895281/

The effect of body temperature on thyroid hormone levels in patients with non-thyroidal illness.

During studies on the mechanism underlying the low serum T3 levels in euthyroid patients with various acute and chronic non-thyroidal illnesses, it became evident that body temperature may be one parameter associated with changes in serum T3 levels. Forty-nine hospitalized, euthyroid patients with hyperpyrexia caused by various non-thyroidal illnesses were studied. The levels of serum T3 were found to decrease gradually with increasing body temperature.

https://www.ncbi.nlm.nih.gov/pubmed/596246

Cancer

Fasting and cancer treatment in humans: A case series report

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815756/

"Short-term fasting (48 hours) was shown to be effective in protecting normal cells and mice but not cancer cells against high dose chemotherapy"

Leukemia, myeloma, and lymphoma (blood cancers)

Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: A randomized, double-blind placebo-controlled cross-over 4g study and an open-label 8g extension study

http://onlinelibrary.wiley.com/doi/10.1002/ajh.23159/full

In this randomized, double-blind placebo-controlled cross-over study, curcumin (4 and 8 g daily) decreased the rFLC (−35 and −36%), iFLC (−8 and −10%), and dFLC (−9 and −11%) in both MGUS and SMM patients

[Note: This gives us a sense of dosing in blood cancers. With regards to bioavailability, there is no mention of piperine in the study. However, it was “administered with a diet containing some fat” in two separate doses.]

Chronic lymphoid leukemia (CLL)/B-cell chronic lymphocytic leukemia (B-CLL)

Turmeric and Green Tea: A Recipe for the Treatment of B-Chronic Lymphocytic Leukemia

http://clincancerres.aacrjournals.org/content/15/4/1123

In this issue of Clinical Cancer Research, Ghosh and coworkers (1) investigate, in the preclinical setting, a novel approach to treating B-chronic lymphocytic leukemia (B-CLL) that combines two naturally occurring compounds, curcumin

The effects of sildenafil citrate on malignant B-cells in patients with chronic lymphocytic leukemia.

http://meetinglibrary.asco.org/content/30588-65

[…] The phosphodiesterase inhibitor sildenafil induces capsase dependent apoptosis of malignant B lymphocytes in vitro. […]

Conclusions: At a dose of 25 to 50 mg weekly, sildenafil does not appear to have any effects on the malignant B cells in CLL. While this dose may not produce a measurable clinical or cellular response, higher doses may still have an effect on the malignant B cells of CLL. The dose of sildenafil was based on a case series of patients with Viagra who had decreases in IgM levels while taking sildenafil 25-50 mg weekly. Subsequent studies in have shown a greater reduction in IgM in patients taking sildenafil 100 mg daily and patients did not report any significant side effects. A follow-up study using sildenafil 100 mg daily is warranted.

[note: phosphodiesterase inhibitors may work best as apoptotic signal enhancers for other therapies]

Phase 2 trial of daily, oral polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia

http://onlinelibrary.wiley.com/doi/10.1002/cncr.27719/full

A total of 42 patients received Polyphenon E at a dose of 2000 mg twice daily [4g EGCG daily] for up to 6 months.

CONCLUSIONS: Daily oral EGCG in the Polyphenon E preparation was well tolerated by patients with CLL in this phase 2 trial. Durable declines in the ALC and/or lymphadenopathy were observed in the majority of patients.

The Effect of Curcumin (as Meriva) on Absolute Lymphocyte Count (ALC), NK Cells and T Cell Populations in Patients with Stage 0/1 Chronic Lymphocytic Leukemia

http://file.scirp.org/Html/3-8902157_57875.htm

Twenty-one patients with significant lymphocytosis (>20 × 109 lymphocytes/L) and stage 0/1 CLL were recruited into the study and received oral curcumin 2 grams/day. […]

Four patients (20%) demonstrated more than 20% decrease in ALC, three of whom had lower ALC at the end of the study as compared to baseline.[…]

A novel curcumin formulation was developed under the brand name Meriva by combining a standardized mixture of natural curcuminoids and lecithin in 1:2 ratio, with 2 parts of microcrystalline cellulose being added to improve the physical state. The relative absorption of a standardized curcuminoid mixture and its corresponding lecithin formulation (Meriva) was investigated in a randomized, double-blind, cross-over human study and total curcuminoid absorption was about 29-fold higher for Meriva than for its corresponding unformulated curcuminoid-like mixture [no mention of piperine]

A Case of Complete and Durable Molecular Remission of Chronic Lymphocytic Leukemia Following Treatment with Epigallocatechin-3-gallate, an Extract of Green Tea

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739749/

In 2015, more than three years after the documented remission, the patient remains well at age 52. He takes epigallocatechin-3-gallate (1200 mg) daily and maintains his self-directed lifestyle regimen.

Apoptosis inducers in chronic lymphocytic leukemia

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964209/

Numerous apoptosis inducers have been described. These synthetic compounds and natural products (mainly derived from plants) display antileukemic properties in vitro and in vivo and some have even been tested in the clinic in CLL. They act through several different mechanisms. Most of them involve proteins of the Bcl-2 family, which are the key regulators in triggering the mitochondrial pathway of caspase-dependent apoptosis. Thus, the Mcl-1/Noxa axis appeared as a target.

cGMP and cancer (exclusionary catchall)

Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826214/

This data provides evidence that the CD95 is a key regulator of sildenafil and DOX mediated enhanced cell death in prostate cancer.

IGF-1 and cancer

Growth Hormone Receptor Deficiency is Associated With a Major Reduction in Pro-aging Signaling, Cancer and Diabetes in Humans

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357623/

we monitored for 22 years Ecuadorian subjects with mutations in the growth hormone receptor gene leading to severe growth hormone receptor (GHR) and IGF-I deficiencies

Curcumin

Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: A randomized, double-blind placebo-controlled cross-over 4g study and an open-label 8g extension study

http://onlinelibrary.wiley.com/doi/10.1002/ajh.23159/full

In this randomized, double-blind placebo-controlled cross-over study, curcumin (4 and 8 g daily) decreased the rFLC (−35 and −36%), iFLC (−8 and −10%), and dFLC (−9 and −11%) in both MGUS and SMM patients

HGH (human growth hormone)

[Effect of phentolamine, diphenhydramine and cyproheptadine on arginine-induced growth hormone secretion (author's transl)].

“It is concluded that either histaminergic H-1 [plus anticholinergic] or both histaminergic and serotoninergic [again, plus anticholinergic] blockade inhibit GH secretion elicited by arginine. On the other hand an alpha-adrenergic pathway in the arginine action is ruled out.”

Influence of different serotonin receptor subtypes on growth hormone secretion.

https://www.ncbi.nlm.nih.gov/pubmed/10686528

"The experiments were carried out on beagle dogs. GH-releasing hormone (GHRH) increased basal canine GH (cGH) levels from 0.8 +/- 0.2 to 8.8 +/- 1.7 microg/l at 15 min. Administration of 5-HT(1D) receptor agonist sumatriptan (SUM) induced a cGH peak at 30 min of 12.9 +/- 2.7 microg/l. The combined administration of GHRH plus SUM strikingly potentiated cGH release with a peak of 36.9 +/- 6 microg/l at 30 min (p < 0.05). Pretreatment with the muscarinic receptor antagonist atropine completely abolished the cGH response to SUM, while the cholinergic agonist pyridostigmine (PYR) did not modify this response (15.3 +/- 5 microg/l PYR plus SUM vs. SUM alone 12.9 +/- 2. 7 microg/l). On the other hand, administration of drugs with activity at 5-HT(2A/C) receptors showed a stimulatory role for the 5-HT(2C) receptor subtype, since LY-53857 (antagonist 5-HT(2A/C)) and DOI agonist (5-HT(2A/C)) both modified the GH response stimulated by GHRH (AUC 88.5 +/- 30.4 and 400 +/- 64.6 vs. 267.3 +/- 52.6 respectively), while ketanserin (antagonist 5-HT(2A)) did not modify this response. The 5-HT(3) antagonist ICS-205-930 failed to modify either basal or GHRH induced GH responses. In conclusion, our data show that 5-HT(1D) receptors play a stimulatory role on GH secretion in the dog, possibly by acting through a decrease in hypothalamic somatostatin release. Similarly, the 5-HT(2C) receptor subtypes also appear to play a stimulatory role. However, 5-HT(2A) and 5-HT(3) receptors do not appear to be involved in the control of basal and GHRH-induced GH secretion."

Effect of tianeptine on the hypothalamic somatotropic axis in the conscious sheep.

https://www.ncbi.nlm.nih.gov/pubmed/7912195

"Abstract

The action of serotonin on growth hormone (GH) secretion is controversial because of interspecies differences and lack of specificity of serotoninergic drugs. Serotonin (5-HT) appears to inhibit GH release in the sheep and in man. We have investigated the site of action of tianeptine, a 5-HT uptake enhancer, in sheep since it is possible to collect hypophysial portal blood for the simultaneous determination of growth hormone-releasing hormone (GHRH) and somatostatin in this species under conscious, unstressed conditions. Tianeptine injection (10 mg/kg i.v.) resulted in a significant, immediate and short-lasting (30 min) increase in peripheral GH (+750%; P < 0.01) and hypophysial portal GHRH (+180%; P < 0.01). No change in the secretion of somatostatin was recorded during the same time. These data suggest that serotoninergic inputs are inhibitory to GH secretion. Tianeptine acts centrally to stimulate GH secretion in the sheep and its effect is mediated through changes in GHRH but not somatostatin release into hypophysial portal blood."

Excitotoxicity

b-12 is neuroprotective (methylcobalamin used in study). http://www.ncbi.nlm.nih.gov/pubmed/9112980

Excerpt from my paper on MDMA:

Excitotoxicity, inflammation, and oxidative stress are all implicated in neurodegenerative diseases.[5] These are interrelated stressors, whereby each of them can instigate the other two. For this reason, it appears that antioxidants lead to protection against MDMA induced serotonergic damage, as well as prevent MDMA tolerance.[6] MDMA serotonergic toxicity was also noted to be associated with reduced antioxidant stores, wherein oxidative stress is known to deplete antioxidant stores.[7] I recommend amla powder (up to 3g daily), as it is a cheap and extremely potent antioxidant.[8] Antioxidant content of one’s diet could potentially explain the the majority of the inter-individual differences in reported MDMA related side effects.

https://docs.google.com/document/d/1LCHxrnpaGkb4rLKbIn6eQqJjQZDHYwLzcYCZq-WTJSg/pub

Inflammation’s role in excitotoxicity.

To start with, multiple sclerosis is associated with a down-regulation in anti-inflammatory genes. In other words, those with multiple sclerosis have more inflammation.

http://www.ncbi.nlm.nih.gov/pubmed/25670004

Furthermore, this inflammation appears to induce glutamate excitotoxicity in multiple sclerosis.

http://www.ncbi.nlm.nih.gov/pubmed/23152401

The treatments for MS are all anti-inflammatory agents.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151595/

Inflammation induced depression may be excitotoxicity mediated.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134384/

As well as schizophrenia.

http://www.ncbi.nlm.nih.gov/pubmed/21707463

Diet

Long chain saturated fat induced insulin resistance (LCSFAs, ceramides, IMTG, DAG, etc)

Effect of Replacing Animal Protein with Plant Protein on Glycemic Control in Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

[Replacing animal with plant protein is often replacing saturated with unsaturated fat in practice. However, it is possible that some of the fat is replaced with carbohydrates. Since carbohydrates are also associated with reduced insulin resistance, it scarcely matters]

http://www.mdpi.com/2072-6643/7/12/5509/htm

Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice

[Mechanism of LC-SFA induced insulin resistance in mice]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083776/

Acute effects of meal fatty acid composition on insulin sensitivity in healthy post-menopausal women.

[Fat induces acute insulin resistance. Saturated dramatically raises insulin. Mostly saturated fat, but applies to other fst. This effect can last to the next meal.]

http://www.ncbi.nlm.nih.gov/pubmed/12493085

Increased intramuscular lipid synthesis and low saturation relate to insulin sensitivity in endurance-trained athletes

[Saturated intramuscular fats are associated with insulin resistance, whereas unsaturated fats are not.]

http://jap.physiology.org/content/108/5/1134.abstract?ijkey=a28ba4b779bf2d1c77bc920975564aa55bec4d31&keytype2=tf_ipsecsh

Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance

[Athletes have increased intramuscular triglycerides and diacylglycerols, but decreased ceramides and improved insulin sensitivity. This suggests that if IMTG and DAG cause insulin resistance, it is minimal compared to ceramides.]

http://diabetes.diabetesjournals.org/content/60/10/2588

Skeletal intramyocellular lipid metabolism and insulin resistance

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762133/

Dietary Fat Acutely Increases Glucose Concentrations and Insulin Requirements in Patients With Type 1 Diabetes

[saturated fat increased postprandial blood glucose and insulin need in type 1 diabetics]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609492/

Differential effects of saturated and monounsaturated fat on blood glucose and insulin responses in subjects with non-insulin-dependent diabetes mellitus.

“The insulin response was significantly increased by adding 50 and 100 g butter, whereas addition of 40 and 80 g olive oil had no effect.”

https://www.ncbi.nlm.nih.gov/pubmed/8561067

Ketosis

Brain changes in BDNF and S100B induced by ketogenic diets in Wistar rats

http://www.sciencedirect.com/science/article/pii/S0024320513001720

http://press.endocrine.org/doi/10.1210/jc.2003-031796

Differential Metabolic Effects of Saturated Versus Polyunsaturated Fats in Ketogenic Diets

Mean circulating β-hydroxybutyrate levels increased 8.4 mg/dl in the POLY group (P = 0.0004), compared with 3.1 mg/dl in the SAT group (P = 0.07). SI increased significantly in the POLY group (P = 0.02), whereas total and low-density lipoprotein cholesterol increased significantly in the SAT group (both P = 0.002). These data demonstrate that a short-term POLY KD induces a greater level of ketosis and improves SI, without adversely affecting total and low-density lipoprotein cholesterol, compared with a traditional SAT KD. Thus, a POLY KD may be superior to a classical SAT KD for chronic administration.

MCT oil

Dietary substitution of medium-chain triglycerides improves insulin-mediated glucose metabolism in NIDDM subjects.

[Edit: upon seeing the full study, the LCT control group appears to use saturated rather than unsaturated fat. Therefore, the relevance is limited.]

https://www.ncbi.nlm.nih.gov/pubmed/1568535

Effect of body fat distribution on the transcription response to dietary fat interventions

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690730/

Medium-chain triglyceride ameliorates insulin resistance and inflammation in high fat diet-induced obese mice. [That is to say, MCT oil is better than lard. Not really that surprising]

https://www.ncbi.nlm.nih.gov/pubmed/25911003

Overfeeding with medium-chain triglyceride diet results in diminished deposition of fat.

https://www.ncbi.nlm.nih.gov/pubmed/6849272

Thermogenesis in humans during overfeeding with medium-chain triglycerides.

[MCTs were over 90% of the 40% total fat diet. 50% calorie overfeeding, so most overfeeding was MCT. It’s worth noting that MCTs elevated triglycerides to a much greater extent than LCTs, which may be sufficient evidence to avoid MCT overfeeding. However, diets with sufficient calories from fat to place in adipose tissue should mitigate the need to elongate MCT, thus making them a fine choice for most normal diets]

https://www.ncbi.nlm.nih.gov/pubmed/6849272

Changes in blood lipids during six days of overfeeding with medium or long chain triglycerides.

In addition, there were increases in 16:1, 18:0, and 18:1 in the triglycerides during MCT feeding. The changes in fatty acids in triglycerides with MCT feeding are consistent with the hypothesis that excess dietary MCT cause a significant increase in the hepatic synthesis of these fatty acids from MCFA through de novo synthesis and/or chain elongation and desaturation. These processes could account for the higher rate of postprandial thermogenesis with MCT as compared to LCT.

http://www.jlr.org/content/31/3/407.short

Medium-chain fatty acids ameliorate insulin resistance caused by high-fat diets in rats [isocaloric]

Insulin sensitivity was reduced by 30% in the LCFA group while the MCFA group did not differ from controls. Feeding MCFA resulted in the controls' lowered fasted and post-prandial triacylglycerol concentration compared to LCFA, while triacylglycerol concentrations in muscle were higher in both high-fat groups compared to controls.

http://onlinelibrary.wiley.com/doi/10.1002/dmrr.925/abstract

De novo fatty acid biosynthesis and elongation in very long-chain acyl-CoA dehydrogenase-deficient mice supplemented with odd or even medium-chain fatty acids.

Previous studies with magnetic resonance spectroscopy have shown an impact of MCT on the average fatty acid chain length in abdominal fat. We therefore assume that medium-chain fatty acids (MCFAs) are elongated and accumulate in tissue as long-chain fatty acids. [this line of research is really limiting my interest in MCTs. I may need to find an alternative.]

https://www.ncbi.nlm.nih.gov/pubmed/26284828

Influence of the dietary intake of medium chain triglycerides on body composition, energy expenditure and satiety: a systematic review.

Thus the results are inconclusive and there is a need for further controlled studies with standardized amounts of MCT, so that its use can become an alternative for obesity nutritional treatment.

https://www.ncbi.nlm.nih.gov/pubmed/22566308

Medium-chain fatty acids improve cognitive function in intensively treated type 1 diabetic patients and support in vitro synaptic transmission during acute hypoglycemia.

https://www.ncbi.nlm.nih.gov/pubmed/1922359

Intermittent fasting.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC156352/

Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake

(alternate-day fasting)

Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake.

Miscellaneous and/or not yet fully categorized.

Avoiding tolerance/reverse tolerance

MDMA reverse tolerance

Can the MDMA roll last forever? A sustainable utopian drug, or a toxic compound for the irresponsible?

https://docs.google.com/document/d/1LCHxrnpaGkb4rLKbIn6eQqJjQZDHYwLzcYCZq-WTJSg/pub

Opiate/opioid reverse tolerance

L-type calcium channel blockers not only prevent opiate tolerance, but causes reverse-tolerance/hypersensitivity.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1572051/

PDE4 inhibitors can prevent tolerance via the same mechanism.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1572651/

Menthol is an L-type calcium channel blocker, but I'm not quite sure of the oral dose required. Menthol is, however, a kappa-opioid receptor agonist, but I've taken grams of the stuff and certainly didn't notice anything as obvious as salvia. In any case, kappa-opioid agonists can also prevent/reverse opiate tolerance.

T-type may work as well.
L-type and T-type calcium channel blockade potentiate the analgesic effects of morphine and selective mu opioid agonist, but not to selective delta and kappa agonist at the level of the spinal cord in mice.

https://www.ncbi.nlm.nih.gov/pubmed/11406339

Kappa-opioid agonism by menthol as an analgesic (as low as 3mg/kg orally in rats).

http://www.ncbi.nlm.nih.gov/pubmed/11897159

Inhibition of the cardiac L-type calcium channel current by the TRPM8 agonist, (-)-menthol.

(-)-menthol concentration-dependently inhibited peak ICa,L (IC50=74.6 µM; log10IC50(M)=-4.13±0.14). (-)-Menthol blocked the late ICa,L remaining at the end of depolarising pulses with greater efficacy (96.1±2.4% block at 1 mM) than peak ICa,L (68.9±5.7% block at 1 mM, P<0.01), although there was no difference in potency of block of peak and late currents. Block by (-)-menthol showed no voltage dependence. [not that I really understand all that, but 74.6 µM translates to 11.65 mg/liter of menthol, or 0.816g evenly distributed through 70kg of person. Since the scale is roughly logarithmic, one tenth that (or 82mg) appears to be around IC20 {20% inhibition}]

https://www.ncbi.nlm.nih.gov/pubmed/21081797

http://www.jpp.krakow.pl/journal/archive/10_10/pdf/543_10_10_article.pdf

100mg/kg injection calcium channel blocking by menthol (it’s worth noting that doses in rats are often insanely excessive). They tested T-type.

http://jpet.aspetjournals.org/content/343/3/661.long

Kappa-opioid agonism prevents opiate tolerance.

http://www.ncbi.nlm.nih.gov/pubmed/20663033

Repeated low doses of morphine do not induce tolerance but increase the opioid antinociceptive effect in rats with a peripheral neuropathy

http://www.sciencedirect.com/science/article/pii/0006899390915899

The importance of the number of NMDA receptors in the development of supersensitivity or tolerance to and dependence on morphine.

So, in light of the previous findings and the present experimental data it can be said that: (1) supersensitivity to opioids may be a downregulation of NMDA as well as an upregulation of the opioid receptor; (2) either upregulation or downregulation of NMDA receptors may facilitate subsequent development of opioid dependence; (3) tolerance to opioid may necessitate both upregulation of NMDA receptors and downregulation of opioid receptors; and (4) beneficial effects of opioid antagonists in the treatment of opiate dependence and CNS injuries may be strongly related to the down regulation of NMDA receptors.

https://www.ncbi.nlm.nih.gov/pubmed/10208762/

Macro-nutrients, Keto/high-carb, calories, insulin, diabetes, etc.

Macro's effect on, glucose score, insulin Index,

https://optimisingnutrition.wordpress.com/2015/06/29/trends-outliers-insulin-and-protein/

Topical and oral menthol thermogenic in humans.

Insulin.

PUFAs increase insulin sensitivity when substituted for saturated fat.

Vanadium still works in ketosis!?

Insulin injections induce ketosis due to hypoglycemia.

Insulin resistance

Different LCTs induce various insulin resistance.

Extreme keto dieting: Drugs for keto etc. Insulin included.

Lecithin inhibits lipid and "bile salts" absorption.

protein used to make glucose from fat? Another description from livestrong.

400g protein (normally) turnover daily.

High and low carb provide mood benefits, but high carb enhanced cognitive processing speed.

http://ajcn.nutrition.org/content/86/3/580.long

High carb diet increases nocturnal energy expenditure as compared to mixed diet. (doesn't specify values, full text link broken 8/25/15)

http://www.ncbi.nlm.nih.gov/pubmed/7037049

As far as fat being processed by the liver, this is true for ketones. However, you've probably heard of "brown fat", which is a tissue that burns fat for heat. Furthermore, intramuscular triglycerides can be used by muscle cells.

https://en.wikipedia.org/wiki/Intramuscular_fat

Similarities of Carbohydrate Deficiency and Fasting

I.  Weight Loss, Electrolyte Excretion, and Fatigue

http://sci-hub.cc/10.1001/archinte.1963.03860030087006

Comparative Effects of Low-Carbohydrate High-Protein Versus Low-Fat Diets on the Kidney

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386674/

[too much protein, like carbohydrates, limits ketosis and its ability to treat diabetes]

https://www.ncbi.nlm.nih.gov/pubmed/23680948

muscle + exercise

estrogen beta agonists for muscle.

http://www.bodybuilding.com/fun/southfacts_methoxy.htm

Anabolic effect of ecdysterone strong enough to put it on the doping list

http://www.ergo-log.com/anabolic-effect-ecdysterone-doping-list.html

flax lignans promote muscle growth

http://www.sciencedirect.com/science/article/pii/S1671292708603661

They noticed decreases in a particular ion channel called HCN4, one of four known “funny channels.” . . . funny channels are key pacemakers that help to determine heart rate. [this suggests that not all mechanisms of reduced heart rate in athletes are good]

https://www.sciencenews.org/blog/scicurious/slow-heartbeat-athletes-not-so-funny

It is common for well-trained people to feel a bit lightheaded when moving quickly from a squat to stand

http://www.runnersworld.com/ask-the-sports-doc/is-my-resting-heart-rate-too-low

The average resting heart rate is 66 to 72 beats per minute (bpm). A well-trained endurance athlete has a resting heart rate of 40 bpm. Miguel Indurain, a five-time Tour de France winner and Olympic gold medalist in 1996, recorded a resting heart rate of 28 bpm. In the mountain stages of the Tour de France, Indurain could take his pulse rate up to 190 beats per minute an[bdnf]d drop it back to 60 on the descent within half a minute.

http://news.nationalgeographic.com/news/2004/08/0820_040820_olympics_athletes_2.html

[Resting heart rate reached by ~5 min after exercise, both pre and post training]

https://www.sportanalytix.com/en/content/1017-heart-rate-recovery-hrr.htm

Exercise and the autonomic nervous system.

There is now convincing evidence that some of the protective and therapeutic effects of chronic exercise training are related to the impact on the autonomic nervous system.

https://www.ncbi.nlm.nih.gov/pubmed/24095123

Effects of exercise timing on sleep architecture and nocturnal blood pressure in prehypertensives

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270305/

Effects of resistance exercise timing on sleep architecture and nocturnal blood pressure.

https://www.ncbi.nlm.nih.gov/pubmed/25426516

http://sci-hub.cc/10.1519/jsc.0000000000000750

Cerebral autoregulation dynamics in endurance-trained individuals

A delayed onset of autoregulation with a larger normalized transfer gain conforms to a less effective dampening of MAP [mean arterial pressure] oscillations, indicating that athletes may be more prone to instances of symptomatic cerebral hypoperfusion when MAP declines.

http://jap.physiology.org/content/early/2011/02/28/japplphysiol.01497.2010.long

Protein turnover, amino acid requirements and recommendations for athletes and active populations

The muscle free amino acid pool in a normal male weighing 70 kg has been calculated to be about 86.5 g excluding taurine and 121.5 g including taurine (3)... Of the total pool of human skeletal muscle free amino acids, the eight essential amino acids (EAA) represent only 8.4%, whereas glutamine, glutamate, and alanine constitute nearly 79%.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854183/

Protein and Muscle (an excerpt from an incomplete blog post I was writing)

In order to maintain most men’s masculine morale, muscle is a must. While a high protein diet may conditionally contribute to muscle synthesis, this actually appears to have almost nothing to do with amino acid supply (1). Take, for example, the fact that removing non-essential amino acids has little impact on muscle synthesis (1), even though muscle proteins are composed of about half non-essential amino acids.

Muscle protein synthesis is, for the most part, easily saturable. What I mean by that is that one can max out muscle protein synthesis with just 20g protein (1), or 10g essential amino acids (1). Adding carbohydrates to a smaller amount of protein can contribute to maximizing muscle synthesis (6g protein + 35g carbs. 1), but provides no additional benefit if muscle synthesis has already been saturated with 20g protein (1). This suggests it is relatively easy to saturate muscle synthesis, and that protein frequency is more important than protein quantity. Some studies in bodybuilders do find benefit from increased protein intake (citation needed), but I would wager this is due to increased protein frequency rather than quantity. Additionally, protein may be more important when insufficient calories are consumed (citation needed).

Conclusions: to maximize muscle synthesis, there is no need to eat more than 20g protein per sitting, and less is sufficient provided coingestion of carbohydrates.

antioxidants and oxidative stress

Exogenous antioxidants—Double-edged swords in cellular redox state

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952083/

sleep drugs and biochemistry

Mirtazapine dose dependent sleep architecture improvement.

https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=14&cad=rja&uact=8&ved=0ahUKEwj-p9OqkNrLAhVG92MKHUkbAUQQFghlMA0&url=http%3A%2F%2Fwww.med.ucla.edu%2Fmodules%2Fxfsection%2Fdownload.php%3Ffileid%3D967&usg=AFQjCNECO1oFpfpOgUyO7ComFIFs38auXg&sig2=Fxt70wTdnAYNTpRpZWWpcw

thp mega info L-thp http://www.mindvox.com/pipermail/ibogaine/2007-May/030730.html

WARNING: Potential risk of hepatotoxicity (toxic for the liver). I was taking this for insomnia. It was very impressive at assisting sleep onset. I was still playing with dose and timing when I had to quit because my blood test showed liver enzymes were high. I pinned down L-THP as the most likely culprit, so I had to stop taking it. My liver enzymes have since returned to normal. I was taking what some people might consider a high dose, 100mg-200mg (0.1g-0.2g). Apparently I didn't do my research well enough. I knew L-THP was hepatotoxic in extremely high doses (i.e. > 1g), but apparently there are cases hepatotoxicity at normal doses as well. I don't know if it would work in this case, but milk thistle extract can often protect the liver. Here is a study on the mechanism of L-THP hepatotoxicity. http://www.ncbi.nlm.nih.gov/pubmed/20109541

Here are some case reports. http://www.cdc.gov/mmwr/preview/mmwrhtml/00022295.htm

Interestingly, the wiki page says “Tetrahydropalmatine has been demonstrated to possess analgesic effects and may be beneficial in the treatment of heart disease and liver damage” and “chronic hepatitis has been reported, caused by THP production in East Asia under conditions that were insufficiently sterile. [no citation provided]

cGMP enhances light induced phase advances (waking up earlier), and may not inhibit phase delays (waking up later) in mice (nocturnal). Update: I think it synergises with light. Free running period was not tested.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037121

Melatonin raises cGMP in humans.

http://joe.endocrinology-journals.org/content/163/3/457.full.pdf

cGMP levels raise during sleep in humans.

http://www.ncbi.nlm.nih.gov/pubmed/10447311

In mice, midnight (should be noon in humans) cGMP radically advances the circadian clock.cGMP advanced to clock to precisely 6am (6pm in humans)

http://www.pnas.org/content/86/17/6812.full.pdf

Another with more details I don't yet understand.

http://www.jneurosci.org/content/17/2/659.full.pdf

non-flushing b3 (niacinamide/nicatinamide) 3g/day improve rem and improve sleep efficiency in case studies.

http://www.aasmnet.org/jcsm/ViewAbstract.aspx?pid=26314

Caffeine half life in insomniacs (max 11.4 hours) [x-post "caffeine and theobromine"].

http://www.holisticprimarycare.net/topics/topics-o-z/vitamins-a-supplements/1246-nutritional-treatments-for-insomnia.html

citrus fruit promote peripheral blood flow in cold. (involved a theory. I'm no longer sure this is relevant to sleep)

https://www.youtube.com/watch?v=OBOGIxeCRT0

vasopressin nose sprays increase sleep quality in older subjects

https://selfhacked.com/2016/04/07/need-know-vasopressin-role-chronic-health-issues/#Vasopressin_Overview

Circadian time n. A standard of time based on the free-running period of a rhythm (oscillation). Note: By convention, the onset of activity of diurnal organisms defines circadian time zero (CT 0). The onset of activity of nocturnal organisms defines circadian time twelve (CT 12)

http://www.circadian.org/dictionary.html

cAMP, cGMP (cyclic AMP/GMP) and phosphodiesterase

PDE4 inhibitors can restore sleep deprivation induced cognitive impairment by restoring cAMP.

https://www.sciencedaily.com/releases/2009/10/091026125401.htm

meletonin increases cGMP.

cAMP and cGMP Signaling Cross-Talk

http://circres.ahajournals.org/content/100/11/1569.full

"In a milestone study in 1971, Mills and Smith showed that adenosine increases cAMP in platelets" and "In healthy volunteers, 250 mg caffeine orally three times a day for 7 days reduced platelet aggregation, increased intracellular cAMP [by] upregulated the platelet adenosine A2A receptors."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195739/

[x-post from "caffeine and theobromine"]

Caffeine inhibits forskolin-stimulated cyclic AMP accumulation in rat brain. [and so does, to a lesser extent, theobromine]

http://www.sciencedirect.com.sci-hub.cc/science/article/pii/001429999090231T

bbb (blood-brain barrier)

Diffusion and flow transfer of theophylline across the blood-brain barrier: pharmacokinetic analysis.

http://www.ncbi.nlm.nih.gov/pubmed/6644553

Same full:http://sci-hub.cc/10.1007/bf01061868

for later research and/or oddities.

https://examine.com/supplements/agmatine/

Simultaneous Use of Stimulants  and Opioids (opiates)

Stimulants should be added to a chronic opioid regimen to maximize pain relief and prevent opioid complications.

http://www.practicalpainmanagement.com/treatments/pharmacological/opioids/simultaneous-use-stimulants-opioids

Addiction and Cognition

In contrast to the effects of opioids on cognition, those of alcohol are clear, though bidirectional: High doses disrupt cognitive processes (Ryback, 1971), while low doses can enhance learning (Gulick and Gould, 2007; Hernández, Valentine, and Powell, 1986).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120118/

Crosstalk between GABAB and mGlu1a receptors reveals new insight into GPCR signal integration

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726695/

Trans fatty acids reduce rate of ALA to EPA (EPA turns into DHA).

DHA reduces ALA conversion in rats 100 fold. Brain levels the same.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927474/

Dietary intake and status of n−3 polyunsaturated fatty acids in a population of fish-eating and non-fish-eating meat-eaters, vegetarians, and vegans and the precursor-product ratio of α-linolenic acid to long-chain n−3 polyunsaturated fatty acids: results from the EPIC-Norfolk cohort

[apparent increase in ALA conversion in vegans]

https://www.ncbi.nlm.nih.gov/pubmed/20861171

Medications for the Treatment of Sleep Disorders: An Overview

[Dopamine in treatment of restless leg syndrome]

Historically, both periodic limb movement disorder and restless legs syndrome have been treated with benzodiazepines, particularly clonazepam.37,41 Low dosages of dopamine precursors and dopamine receptor agonists at bedtime have been demonstrated to be efficacious in these disorders. Possible side effects from these medications, which include carbidopa/levodopa, pergolide, pramipexole, selegiline, and ropinirole, are nausea, headache, and occasional augmentation of symptoms.42,43

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC181172/

Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice

http://www.pnas.org/content/105/48/18895.full

sleep posture

Instinctive sleeping and resting postures: an anthropological and zoological approach to treatment of low back and joint pain

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1119282/

Heads Up! The Way You Are Sleeping May Be Killing You

http://www.hawaiireporter.com/heads-up-the-way-you-are-sleeping-may-be-killing-you