Melatonin and sleep-wakefulness: why synchronization of biological rhythms and adherence to daily periodicity is important

Mela­tonin, in the minds of most peo­ple, is a cross between a sleep­ing pill, a dietary sup­ple­ment, and some­thing col­or­ing. The lat­ter is explained by the con­so­nance in name with the pig­ment melanin, which is respon­si­ble for the col­or of the skin and hair in humans. Mean­while, mela­tonin is a hor­mone, which means that it is involved in many process­es in the human body, many of which have lit­tle to do with sleep.

What is melatonin

Mela­tonin is the main hor­mone of the pineal gland, the pineal gland of the brain. It is also pro­duced by lym­pho­cytes and ente­rochro­maf­fin cells locat­ed in the gas­troin­testi­nal tract (GIT) — in par­tic­u­lar, in the pan­creas and hepa­to­bil­iary sys­tem (organs that form bile). More­over, the lev­el of mela­tonin in the intes­tine is 10–100 times high­er than in the blood, and 400 times high­er than in the pineal gland.

Accord­ing­ly, they say:

• epi­phy­seal (cen­tral) mela­tonin and
• paracrine (region­al, periph­er­al) mela­tonin.

If you com­plete­ly block the body’s abil­i­ty to receive cen­tral mela­tonin from the pineal gland, then the periph­er­al one will not go any­where and will con­tin­ue to work. There­fore, sci­en­tists believe that one of the func­tions of mela­tonin is the coor­di­na­tion of cel­lu­lar func­tions at the lev­el of indi­vid­ual organs.

In addi­tion, mela­tonin is the old­est antiox­i­dant (and it is stronger than vit­a­mins C and E), which is found in almost all liv­ing organ­isms on Earth. So along the way, it can per­form pro­tec­tive func­tions, pro­tect­ing indi­vid­ual organs and tis­sues from oxida­tive stress.

Mela­tonin lev­els decrease dur­ing a per­son­’s life for the fol­low­ing rea­sons:

• Elder­ly age.
• Car­cino­gen­e­sis.
• Smok­ing.
• Increased body mass index.

Con­sid­er­ing the issue of using mela­tonin to influ­ence the body from the out­side, we should talk about:

• endoge­nous mela­tonin, which is pro­duced in the body and
• exoge­nous mela­tonin, which a per­son enters in the form of drugs.

Melatonin and biological rhythms

Mela­tonin is a key ele­ment of the “mol­e­c­u­lar clock” of all ani­mals on Earth. The max­i­mum pro­duc­tion of mela­tonin in the pineal gland falls on the dark time of the day (200 pg/ml and more), and the min­i­mum — on the light day (no more than 10 pg/ml). The pineal gland is asso­ci­at­ed with the suprachi­as­mat­ic nuclei of the hypo­thal­a­mus, which are the cir­ca­di­an pace­mak­er, that is, they are respon­si­ble for fluc­tu­a­tions in var­i­ous body func­tions dur­ing the day.

The main task of mela­tonin is the syn­chro­niza­tion of bio­log­i­cal rhythms and the obser­vance of dai­ly peri­od­ic­i­ty. More­over, mela­tonin allows you to build in a sin­gle rhythm not only the “sleep-wake­ful­ness” sys­tem, but also the sys­tems respon­si­ble for mem­o­ry, think­ing, log­ic and human emo­tions — main­tain­ing them in work­ing con­di­tion is part of a healthy lifestyle.

Sci­en­tists believe that it is this abil­i­ty that makes it pos­si­ble to use the exoge­nous mela­tonin prepa­ra­tion to com­bat the man­i­fes­ta­tions of desyn­chrono­sis (dis­tur­bance of dai­ly human bio­rhythms) dur­ing flights between dif­fer­ent time zones, to treat sleep dis­or­ders and some men­tal dis­or­ders.

Other abilities of melatonin

Mela­tonin recep­tors are found not only in the gas­troin­testi­nal tract, but also in the myocardi­um (heart mus­cle), in vas­cu­lar and blood cells. This diver­si­ty indi­cates a high lev­el of mela­tonin ver­sa­til­i­ty. For exam­ple, hor­mone recep­tors have been found on the sur­face of cer­tain immune sys­tem cells. There­fore, it is an immunos­tim­u­lant, and is also involved in the reg­u­la­tion of sea­son­al and lunar cycles in humans.

In gen­er­al, it is a mis­take to con­sid­er mela­tonin a hor­mone that can only be used to treat sleep dis­or­ders. The effec­tive­ness of mela­tonin has been demon­strat­ed in trau­mat­ic brain injury, epilep­sy, Alzheimer’s and Parkin­son’s dis­eases, hyper­ten­sion, angi­na pec­toris, cer­tain types of arrhyth­mia, cer­tain types of depres­sion, eczema, glau­co­ma and cataracts, and also as part of com­plex ther­a­py for cer­tain types of can­cer.

Sci­en­tists are also pay­ing spe­cial atten­tion to the abil­i­ty of mela­tonin to reduce the side effects of var­i­ous phar­ma­cother­a­pies. Mela­tonin is suc­cess­ful­ly used for var­i­ous kinds of intox­i­ca­tion: from drug over­dose to poi­son­ing with indus­tri­al poi­sons or salts of heavy met­als.

It should be remem­bered that mela­tonin is a hor­mone. So, epi­phy­seal mela­tonin can affect the work of some endocrine glands, for exam­ple, the pro­duc­tion of hor­mones by the adren­al cor­tex. That is, we can say that, in addi­tion to its direct effect on many body sys­tems, mela­tonin also has an indi­rect effect, start­ing the pro­duc­tion of oth­er hor­mones.

Melatonin and sleep

Prac­tice has shown that tak­ing mela­tonin prepa­ra­tions real­ly helps a per­son fall asleep. And the low­er the lev­el of his own, endoge­nous mela­tonin, the stronger the effect of the exter­nal, exoge­nous drug. But at the same time, the dura­tion of sleep does not change. But the com­bi­na­tion of mela­tonin with oth­er drugs (ben­zo­di­azepines) improves sleep qual­i­ty, dura­tion, reduces the time to fall asleep and the num­ber of night awak­en­ings.

In addi­tion, the effect of mela­tonin is high­ly depen­dent on what time of day it was tak­en. So, if the patient received mela­tonin in the first half of the night or right before bed­time, then the phase change of his cir­ca­di­an rhythms occurs faster. If the drug was tak­en in the sec­ond half of the night or in the first half of the day, then the phase change of cir­ca­di­an rhythms, on the con­trary, occurs lat­er. There­fore, the best time to take the med­i­cine is the time of 22–23 hours.

Benefits of melatonin preparations

• Safe­ty.

Mela­tonin is not a for­eign sub­stance for our body, we our­selves know how to pro­duce it. There­fore, it is quite safe as a drug — even high dos­es (100–150 mg dai­ly) do not lead to an over­dose.

• Effi­cien­cy.

Mela­tonin is a hor­mone. Even in small dos­es (3–5 mg) it gives a real clin­i­cal effect, for exam­ple, in the fight against insom­nia.

Disadvantages of melatonin preparations

• Lack of evi­dence for safe­ty and effi­ca­cy.

Too few obser­va­tions have been made when tak­ing the drug, so that it can be con­sid­ered with 100% cer­tain­ty that it is absolute­ly safe and, more­over, effec­tive.

• Atyp­i­cal depen­dence of the effect on the dose of the drug tak­en.

For most drugs, depen­dence is observed: a larg­er dose — a stronger effect, up to an over­dose. Not every­thing is so sim­ple with mela­tonin: start­ing from a cer­tain dose, the effect not only decreas­es, but can even take on neg­a­tive val­ues. Dur­ing the exper­i­ments, it was found that at cer­tain dosages, mela­tonin, which had just pro­tect­ed against oxida­tive stress, on the con­trary, began to increase stress man­i­fes­ta­tions. Accord­ing to oth­er stud­ies, the hypno­genic effect of mela­tonin will be high­er if you take a dose 10 times small­er than what is rec­om­mend­ed by doc­tors today.

• The need to ana­lyze the ini­tial hor­mon­al back­ground.

Since mela­tonin is pro­duced by the per­son him­self, before pre­scrib­ing its intro­duc­tion from the out­side, it is nec­es­sary to deter­mine not only the con­tent of the hor­mone in var­i­ous human bio­log­i­cal flu­ids, but also to cal­cu­late the curve of the dai­ly pro­duc­tion of epi­phy­seal mela­tonin.

• dura­tion of treat­ment.

To achieve a real effect, long cours­es of treat­ment (3–4 months) are required.

• Weak direc­tion­al effect.

Mela­tonin works best in com­bi­na­tion with oth­er drugs, more tra­di­tion­al for the treat­ment of the same insom­nia.

• Lack of con­trol.

Mela­tonin is involved in a huge num­ber of bio­chem­i­cal process­es in the body. It is impos­si­ble to con­trol them com­plete­ly. But you need to under­stand exact­ly that when tak­ing a hor­mon­al drug, we trig­ger dozens, if not hun­dreds, of reac­tions, most of which we actu­al­ly do not need at the moment.

conclusions

• Mela­tonin in the body is designed main­ly to adapt to chang­ing envi­ron­men­tal con­di­tions. In ordi­nary life, it should be used to treat desyn­chrono­sis and to adapt to night shift work.
• It is best to use mela­tonin as an addi­tion­al drug as part of com­plex ther­a­py.
• You can not pre­scribe your­self mela­tonin on your own, with­out exam­i­na­tion and tests, with­out the rec­om­men­da­tions of a neu­rol­o­gist.
• You should not only care­ful­ly cal­cu­late the dose, tak­ing into account the mass of influ­enc­ing fac­tors, but also take the drug at a strict­ly defined time of day, so as not to get the oppo­site effect.

Expert comments

Mashilov Stanislav Kir­illovich, neu­rol­o­gist of the net­work of med­ical cen­ters I CURE

Mela­tonin prepa­ra­tions have been wide­ly used in clin­i­cal prac­tice since their appear­ance. The main indi­ca­tions for its appoint­ment are the so-called “desyn­chronoses” (“jet lag”) — sleep dis­or­ders with a rapid change in time zones as a result of flights, as well as due to work on night shifts.

In sleep dis­or­ders not relat­ed to the above rea­sons, the effec­tive­ness of this drug seems to be very mod­est. How­ev­er, mela­tonin is con­sid­ered as a treat­ment for sleep dis­or­ders in the elder­ly asso­ci­at­ed with age-relat­ed changes in the metab­o­lism of this hor­mone in the body (again, if insom­nia is not asso­ci­at­ed with oth­er patho­log­i­cal con­di­tions). When tak­ing mela­tonin on a course, it is impor­tant to remem­ber that the opti­mal time for tak­ing it is 22–23 hours, which cor­re­sponds to the dai­ly rhythm of its pro­duc­tion in the body. In gen­er­al, the drug has not estab­lished itself as a “panacea”, and its appoint­ment requires a clear def­i­n­i­tion of indi­ca­tions.

Sum­ming up, I would like to say that sleep dis­or­ders, espe­cial­ly long-term ones, are char­ac­ter­ized by a large vari­ety of caus­es, there­fore their treat­ment is a com­plex task, requir­ing a care­ful and ver­sa­tile assess­ment by the doc­tor of the patien­t’s con­di­tion.

Sergey Alexan­drovich Beshkarev, neu­rol­o­gist, CDC Med­si

I will answer the main ques­tion right away — of course, “for”, “against” — only if there is no effect from the drug. The drug Melax­en (active ingre­di­ent mela­tonin) works great, espe­cial­ly in young and not “neglect­ed” patients. And then, the mean­ing of the word “against” is not that the drug will harm the patient or have some side effects, but that in the absence of the effect of mela­tonin in this par­tic­u­lar per­son, it is nec­es­sary to solve his prob­lem with dis­turbed sleep more wide­ly. and com­plex than just tak­ing a drug that pro­motes falling asleep.

Has any­one won­dered what the main phys­i­o­log­i­cal cause of sleep dis­tur­bance is? My prac­ti­cal expe­ri­ence shows that for the first time a sleep dis­or­der occurs in peo­ple in the range of about 40–50 years. True, now the low­er lim­it of age against the back­ground of the real­i­ties of our life tends to decrease.

The fact is that by the age of 35–40, many peo­ple expe­ri­ence sig­nif­i­cant changes in the cer­vi­cal spine of a degen­er­a­tive nature, while the blood flow through the ver­te­bral arter­ies, which sup­ply blood to the auto­nom­ic cen­ters of the brain, is pro­nounced­ly affect­ed. And sleep is a man­i­fes­ta­tion of a nor­mal­ly func­tion­ing auto­nom­ic ner­vous sys­tem. Under con­di­tions of chron­ic hypox­ia of the veg­e­ta­tive cen­ters and, above all, the hypo­thal­a­mus, due to defi­cient blood sup­ply to the brain through the sys­tem of ver­te­bral arter­ies, dis­turbed sleep becomes one of the first man­i­fes­ta­tions of seri­ous mal­func­tions in the auto­nom­ic ner­vous sys­tem. These are the cas­es when mela­tonin does not help.

There­fore, in a 40-year-old per­son, tak­ing into account the age and indi­vid­ual degree of “wear and tear” of the cer­vi­cal spine under con­di­tions of per­ma­nent stress, over­work, with a rather long win­ter and a long absence of sun in our geo­graph­ic lat­i­tudes, the prob­lem of improv­ing sleep should be approached some­what dif­fer­ent­ly. In any case, it has been noticed that those who reg­u­lar­ly work out in the gym “for health” have prac­ti­cal­ly no prob­lems with sleep dis­tur­bance.