About melatonin - 1996

Published on Monday, 03 December 2012

Prof. Luigi Di Bella - About Melatonin - 15/Jun/1996 - Congress Monza (Italy)


Melatonin - 3D structure

Particularly numerous are the works published on the effectiveness of Melatonin: In Vitro, In Vivo (Animal Only), Review, Editorial, Meta-analysis, Preclinical Study and In Vivo (Human Only).

Luigi Di Bella has filed for patent to protect the following invention: Method of production of essentially pure melatonin and the method of solubilizing melatonin in water.

  • United States Patent RE35,631;
  • Inventors: Fraschini Franco (Milan, IT), Di Bella Luigi (Milan, IT), Duranti Ermanno (Milan, IT), Duranti Maria Teresa Moni (legal representative, Urbino, IT), Duranti Andrea (legal representative, Urbino, IT), Duranti Lucia (legal representative, Urbino, IT);
  • Assignee: IFLO S.A.S. (Milan, IT);
  • Appl. No.: 08/252,905
  • Filed: June 2, 1994

See below for this patent, click here and/or here.

Below videos and complete transcriptions:

See, also, slides with video at The New York Academy of Sciences (12/Aug/2009) by Steven M. Hill - Molecular Mechanisms of Melatonin's Anticancer Effects. Department of Structural & Cellular Biology, Tulane Cancer Center.


Melatonin - Monograph


About this monograph.



Only In Vitro Research (Isolated organs, tissues, cells, or biochemical systems - IUPAC Gold Book definition)


In Vivo (Animal Only)




Commentary - Editorial - Letter to the Editor - Communication


Meta-analysis, Pooled Analysis and Narrative Reviews


Preclinical Study


In Vivo (Human Only: Case Reports/Series, Clinical Trials, Comparative Studies, Randomized Controlled Trials and Retrospective Studies)


Melatonin 01:



The key aspect of this meeting perhaps is double. On one hand a signal over the scientific matters on the other the aspect of the legal issue.

From the scientific point of view I have dealt since the beginning with this matter, and I still regret to say that the essence of the physiological action of melatonin seems to be very little understood, especially by those who believe that they have sensed it, in the fullness of its action!

In an article that will be published soon, I have summarized the action of melatonin as that of a complex determinant of what we can call APUD system: Amino Precursor Uptake and Decarboxylation.

In other words, the system of the production and continuous exchange of the radical NH2 COOH by certain substances that are highly important for their actions, more or less specific at the level of the central nervous system and which can, by changing some of the radicals one with the other, implement some impressive modifications of the whole activity, physiological on one hand, pharmacological on the other from another point of view. I have spoken of APUD in which melatonin plays a key role!

So the APUD system of melatonin which until now had not been considered nothing more than adrenaline, noradrenaline then the 5-hydroxytryptamine (serotonin), but melatonin has not been considered then that is the one that holds the strings of all of these chemical mediators. So APUD system and melatonin.

The second most important thing that would be appropriate that all researchers should keep on melatonin, is this: The melatonin that we find in the blood plasma, and that indirectly we want to dose through glucurono or sulfur-6-conjugation in urine and respectively in the salivary glands, this melatonin is a part of the melatonin!

Because melatonin travels inside platelets and the platelet is the main vector of melatonin. So, speaking of melatonin regardless of what is the metabolism, the creation, the process of building, action and destruction of the platelet, means not understanding almost anything of what is the action of melatonin.

The results. Of course the first thing was the experimentation about which we published a few years later Progress in Brain Research Journal, one of the most prestigious newspapers and we communicated to the Royal Academy of Sciences in Amsterdam, the change in rate of platelets as a result of the stimulation of the habenular nucleuses. We have stimulated the median and lateral nucleuses of the habenulae.

The fundamental result of this was that in 12 rats that started from an average of about 200,000 platelets per cubic millimeter, during stimulation of the nucleuses of the habenulae there was an increase in the rate of platelet circulating up to 600,000, three times as much, an increase of 300%, however, this increase lasted relatively little because within 72 hours everything returned to the previous point. The core and the reason of the further researches derive from these researches that were experimental.

From all this the first deduction from the therapeutic point of view was: "What to do with this melatonin and where can it be applied? Why melatonin and not serotonin?". Because I stimulated the habenular, but about habenular was beginning then to inquire what importance thay had for the innervation of the pineal gland.

European Pineal Study Group Giessen - 1981We were in the period in which Ariens Kappers who was president of the Royal Academy of Sciences in Amsterdam, did his research on the innervation of the pineal, and Okshe of the University of Giessen comparative anatomy, did his research on the the relationships that there could be among the visual receptors, photoreceptor cells on one hand and the pineal on the other. Now this is a topic that has been widely debated and exhausted.

However we know that a quantity of elements of the pineal, pinealocytes cells, have, under the most biochemical than morphological structural profile, tight relationship with cones, with the rods and with photoreceptor cells.

From here a series of searches: light-melatonin, dark-melatonin, relationship between sleep and waking, between day and night, a mass of research has been done, however, by people who did not understand the reasons why it was reached this point here. That said, do some research a bit as if there were some limits of vision of the problem.

Then the reason why I have used the melatonin was because serotonin is very little usable. We all have the serotonin. We knew then this fact here, that serotonin however great may be the concentration in the circulation, I mean the serotonin in the plasma, this ends almost all inside platelets.

There are mechanisms that affect an increase of the concentration of serotonin inside the platelets in the order of 400-500 times in the platelet. So there are mechanisms, of course all those studying these mechanisms not all of the results have been univocal, however, that there is this huge increase in platelets is a fact!

But serotonin is apparently close to melatonin. The difference is that the carbon atoms one on one side and three on the other. The hydroxyl radical (HO) is methylated, but what's in this methylation though! On the other hand, the located carbon atom is nothing less than acetylated, but also this acetylation process is a spectacular process under this aspect.

However, melatonin is a substance that can receive methyls (-CH3) and we know which are the substances that prefer to give the methyl and then give later then melatonin. But melatonin also receives the acetyl radical and here is a story that is great, we still have not finished the research on this fact, but there is a radical acetyl. So the secret action of melatonin is all here!

It can be briefly summarized saying: Thee melatonin must not be found for its effects to what is the chemical structure, but for what concerns the reactions which give rise to,reactions that if it were not for the melatonin APUD system has no reason to exist and this can occur in many tissues, the system APUD, especially at the level of the termination of the so-called nervous system of the vegetative life and at the level of the organs that are innervated by this, but it can also be detected elsewhere.

Platelets are the smallest, the most perfect, the most whole APUD system! And this here is present everywhere and is ubiquitous because the platelet is everywhere! This here is the first secret to know what is the mechanism of action of melatonin in this case we are talking about here.

Another mechanism of action of melatonin that is relatively little understood: We give melatonin and many times the patients who come to me say: "I bought the melatonin from that guy, or another, etc.".


Melatonin 02:



The very simple reason was this: at the time when I began prescribing melatonin, I bought the first 200 grams at my own expense and went broke, and with this melatonin I had bought I didn't know how to dissolve it, because it doesn't dissolve in water, it doesn't, it just floats and in all the different ways I tried I just couldn't manage to dissolve it!

So I had this idea that I got from reading that Bradsher had been working in the La Roche Scientific Laboratory, he who most probably gave the greatest contribution without realising what he was doing!

The contribution was the following: Serotonin first and then melatonin are capable of forming bonds, the so-called hydrogen bonds, with these substances, a certain type of substance.

During the second last conference in Birmingham there it was, and as soon as I found it I immediately got hold of it, a very fine treatise: "Hydrogen Bond". It's rather heavy and unwieldy, and I haven't read it yet as it's difficult difficult to understand, nevertheless "The Hydrogen Bond".

In the general chemistry that we studied, we also had considerable difficulties partly because we had to use specified hydrochloric acid, hydrochloric acid (HCl), as to hydrogen this has to be "heavy hydrogen" I mean it is not specified and we had some difficulties due to it coming from Canada!

In other words, thanks to what we did we proved that if hydrogen is not bonding with adenosine, melatonin is not as effective as it is! Thus the other second action, is also this: The bond of hydrogen with adenosine is a fundamental fact in order to understand the way it works!

Whenever I can, in order not to burden the poor patients I actually say that adenosine may also be used, but it is a completely different thing!

If I had the means then I could produce melatonin from adenosine and serotonin, but if I haven't got any then I can't do a damn thing!

Not only that, sometimes melatonin is active, such as in platelet formation, and sometimes it isn't, and why is that? Because there are also all the various enzyme systems that are responsible for this.

A bond of hydrogen is a bond that has a tiny quantity of energy: thus it is estimated that for a millimole we need three thousandth of a calorie in order to be activated and deactivated respectively. Therefore extremely small quantities.

Moreover it is the amount of time taken by this bond, it's something in the region of a billionth of a second.

The author of the book I was mentioning actually comes to this conclusion: "Without the hydrogen bond life would be impossible!".

We are looking at a bond standing in between the bond of Van Der Waals on one side and the bond of Electrovalency on the other, and it is a bond which has infinite possibilities, but in absence of this kind of bond melatonin wouldn't be what it is, and the action of melatonin wouldn't be that which we are accustomed to use it for!

In other words melatonin is a word, but we must see how it works and in what conditions it is found. When someone calls me up on the phone asking: "I have taken melatonin and I am affected by such and such I must take treatment for a certain cancer etc.". I very simply answer and as I've very often said: "Melatonin doesn't cure any tumor but without melatonin there is no possibility to be cured!". It is a necessary but insufficient condition!

The melatonin that we prescribe has to enter the APUD system and particularly that of the platelets, if it doesn't reach the APUD system level the action can even be null.

Fortunately nature is much greater than all that goes on in our minds, so even if we act in a wrong manner nature provides so that melatonin is able to act, and that action can take place by means of all those systems which we fail to think of with our own minds but which nature implements spontaneously.

Therefore, at this stage, the other last important thing, also from the practical point of view, is this. Today we prescribe great quantities of platelet aggregation inhibitors being very much fixed on this idea.

My own view is quite different, and there are some doctors here who sometimes ask me: "They have prescribed platelet aggregation inhibitors but is this what they are used for? Is it absolutely necessary that I prescribe the platelet aggregation inhibitors?".

We have forgotten something crucial: Platelets are fundamental for endothelial tropism! What else needs to be said! It's fundamental because the platelet is not just what we think it is, namely, the crucial element for blood coagulation.

When Giulio Bizzozero discovered it in the late nineteenth century, he said: "Yes I realised it was crucial for blood coagulation, but amongst the many actions performed by platelets, there is also that of blood coagulation!", but that's certainly neither the only nor the most important of the actions performed by melatonin. We must remember that there is the endothelial tropism!

Endothelial cells perform many functions indeed! From a chemical-physical standpoint, endothelium means permeability. Permeability means exchange. Exchange means nutrition, it means function, from every aspect.

It also means this fact: the production of what is called the 'Endothelial Factor' of contraction and release respectively. 'Relaxing and Contracting Factor'.

There are two principles totally different from one another, but if the platelet is not there, none of these are formed! Moreover there is also the DPC, which forms melatonin itself.

This substance develops an effect that produces leiomyomata. A great quantity of what up to now we have treated as atherosclerosis are but tiny leiomyomata, at the arteries' middle-coat level, caused by this fact of the platelets themselves. Platelets are 'extremely dangerous blasters' but also a determining factor!

Melatonin, as I've said before and talked about at many conventions, is the most physiological platelet aggregation inhibitor. The platelet is present and performs its action all the way through because melatonin is present, that preserving it and allowing a gradual, localized destruction, thus releasing all those fundamental substances contained in the platelet, no less than to the entire endothelium!

But as to the endothelium we calculate that there are many square metres of endothelium, with all the endothelial capillaries present. It is not only the surface that is involved but also molecules, because these actions work at molecular level, that's the other action, let's call it the trophic action carried out by melatonin.

Now, also in the works that you, Dr. Lissoni and others, have carried out, which I've had the opportunity to read, you have highlighted everything that goes on in terms of the platelet-rate, but how many times, due to the many chemotherapy treatments, do we see white and red blood cells fall as well as platelets!

And platelets are what we are most afraid of! Indeed a platelet transfusion can be done, but how long does a platelet last within the blood circulation? It's four hours or maybe just four days and after that? ...and after that?


Melatonin 03:



Melatonin maintain for several reasons because blocks the whole system which is located in the level of the membrane. The platelet meanwhile lasts because it is possible to keep the whole membrane and this can occur only because there is melatonin!

If it were not for melatonin the life of a platelet that normally, we believe, that it can last from a minimum of 3 to a maximum of 12 days, the turnover of the platelet should be exceptionally fast, not only, but you should have the release of all the substances in the platelet and then the impoverishment of all substances. Melatonin preserves the platelet, increases the duration of action. Decreases the work of production of platelets. Therefore already a whole mass of action, a large part of these actions have yet to be reviewed.

With regard to the specific fact, the use in cancer. I got to this point by chance. The case was simply this. I was invited by a friend who was an assistant at the institute, whose father was affected by tumor, his conditions were desperate! It was a lung tumor which apparently had metastasized to the spine, however the necessary​ bone scans were not done, he was unable to move etc! The result was magnificent with this therapy! This was the first case!

Of course, after this more cases arrived. For example a tumor of the stomach for which the surgeon opens and closes because he felt it was impossible to operate! With that surgeon I had done two years of university together so I knew him well. I spoke with him, he told me that it was inoperable, this is the reason why he opened and closed!

Well, this person lived afterwards with melatonin, and with all the rest of which I will speak later, for 17 years in perfect conditions! He was a farmer, he never refused to do any work. He died later on but not for stomach cancer: distressed by his daughter's marital problems, he died because of his heart. However he lived 17 perfect years!

Then more cases came! For example of malignant non-Hodgkin's lymphoma, always from a nearby town, in the center of Sicily (Italy). She had completed the first cicle of chemo at the Cancer Institute in Milan, after which she went back and forth. To remove also in economic and financial terms, the expenses of the family (which were considerable) again I suggested melatonin, which I was already perfecting along with the rest, to this girl. Periodically, whenever the deadline for having to do the so-called cycle, from the Cancer Institute somebody would call: "But, you did not come!?". At one point the one that rang from the Cancer Institute said: "But, the lady 'So and So', is she dead?". "No!" - she said - "It's me!" she answered! She never went back to the Cancer Institute! She is well, got married, gave birth to three children, she teaches, she makes a living honestly and so on.

The researches and subsequent experiences have been made in this manner. Well, not that I had a hospital or a clinic but the results are the latter. No more than a month ago after 3 weeks of treatment, a 73 years old Piedmontese: a tumor that spread mainly to the ileum of the right lung; after 3 weeks there was no more trace of it!

There is another person who works for the Ministry of Health, which found itself in a similar situation! Here too, after 3 months all traces of metastasis were gone! Therefore there are successful cases.

Of course it is not one case, two cases that can make a law, however when I am asked how many cases of non-Hodgkins malignant lymphoma I have treated: "It is necessary to come up with statistics!", which is the strength of crooks! The statistics!

For me it would be enough one positive case in a million negatives, not to say that it is law but to say: "I must take the inspiration from what has been done to achieve healing in this case!". "Let's study!".

All other remarks received answer from none other than Ward in a conference that has been published for Ciba Symposium: "Not to use a compound because it has still to get the pharmacological review!". He consider it: "A misconception!". We have data that sometimes the clinician can show us, the pharmacologist can only specify but not replace, who tell us that we can prolong life and it is not little, save a person, remove the danger of death! Nowadays, after the results that have occurred, to continue treating as it has been done till now is a mistake! Is a misconception! I'm done and thank you.