Ritanserin - Serotonin Antagonist For R&D Use Only

[Waynish]

I know, the fluorine bothered me as well but I could not find any reports of liver or thyroid toxicity. It is the chlorine atoms in second-generation antihistamines that make them liver-toxic. For the record, even cypro has recorded liver toxicity but not ritanserin. Quite the opposite actually, ritanserin seems to protect the liver, even in cases as serious as cirrhosis.

It's not in stock currently. Also, if you look at the other posts I am not very keen on keeping selling it as there is not much unique effect to it and Peat is concerned about the fluorine molecules in it.

These don't seem to jive - why the change of heart? People seemed to like it... Anyone find good sources?
Thanks!

 

[haidut]

These don't seem to jive - why the change of heart? People seemed to like it... Anyone find good sources?
Thanks!

They do jive - one of them was my opinion and the other one is Peat's. He told people he absolutely does not recommend it. So, out of caution and since sales dropped to almost zero we decided to discontinue it. It was also quite expensive to buy and took a long time to wait for and ship/deliver. Metergoline is also a non-specific serotonin antagonist with dopaminergic properties and seems to be much less prone to side effects due to its structure and decades of clinical usage track record.

 

[VelvetNerves]

Thoughts on MIN-101 - Wikipedia? It's one of my favourite upcoming atm

 

[Texon]

Inhibit what? ACTH? PNMT? The stress response?
Well, avoid stress, like Mufasa hinted. Pregnenolone may lower CRH, which is the starting point of the cascade but ACTH can also be stimulated by estrogen and prolactin. So, vitamin E, aspirin, niacinamide, glycine, calcium, vitamin D, vitamin A, should all help. Anti-serotonin drugs definitely lower ACTH, so that's another option.

@Travis @tyw Haidut et al, have you guys seen this?

Excess nicotinamide increases plasma serotonin and histamine levels. - PubMed - NCBI

If so, what is your take regarding this study/outcome?

 

[InChristAlone]

@Travis @tyw Haidut et al, have you guys seen this?

Excess nicotinamide increases plasma serotonin and histamine levels. - PubMed - NCBI

If so, what is your take regarding this study/outcome?

It doesn't really make sense because Dr Hoffer had like an 80% cure rate for schizophrenia by using high dose niacin.

 

[haidut]

@Travis @tyw Haidut et al, have you guys seen this?

Excess nicotinamide increases plasma serotonin and histamine levels. - PubMed - NCBI

If so, what is your take regarding this study/outcome?

Search the forum, this study has been posted and discussed many times.

 

[Texon]

Search the forum, this study has been posted and discussed many times.

Ok I will thanks.

 

[Travis]

@Travis @tyw Haidut et al, have you guys seen this?

Excess nicotinamide increases plasma serotonin and histamine levels. - PubMed - NCBI

If so, what is your take regarding this study/outcome?

This study actually has a free full-text researchgate.com edition:

Tian, Y. "Excess nicotinamide increases plasma serotonin and histamine levels." Acta Physiologica Sinica (2013)​

I like this Asian scientist, and had read his earlier article on niacin and methyl groups. It turns out that nicotinic acid can rightly be seen as a methyl acceptor (by analogy to a methyl donor, of which niacin does the opposite):

He gives subjects a stiff niacin dose and then measures two methylated niacin metabolites in the urine, which look like this:

I think it would have been nice if he would have drawn a curve to fit the data, and then had integrated that curve, to find the total methyl groups excreted over that time period; you could subtract this from the baseline (extrapolated from the initial value), and them compare it the the reduction of betaine and choline observed (each of which has three methyl groups).

Choline is the precursor for acetylcholine, and all brain-derived acetylcholine comes from serum choline.⁽¹⁾ It's a good think that betaine is 'the better methyl donor,' or high-niacin people would have more to worry about than the increase in serotonin:

Although this study is primarily concerned with counting methyl groups, the rise in sertonin is probably best explained through the kynurenine pathway. True that serotonin can be methylated—i.e. methoxytryptophol, methoxyindolacetic acid, melatonin—but those are relatively minor metabolites. I personally think it's enough to say that niacin spares tryptophan, either through direct enzyme inhibition or a genetically-driven mechanism (a niacin sensor?). However this occurs, classic Pellagra research and dozens of subsequent studies will confirm that this occurs.

'Niacin is usually classified as a B vitamin. However, strictly speaking, it is not a vitamin because it can be synthesized from tryptophan.' ―Tian​

So niacin starvation may be anti-metabolic by lowering NAD⁺, NADH, NADP⁺, and NADPH—which are the the №1, №2, №3, and №4 metabolic enzyme cofactors in the body—but can be anti-serotonin as well; a deficiency in NAD⁺/NADH will force the body to cleave tryptophan's indole ring to form the pyridine of nicotinic acid necessary for enzymatic cofactors. Interferon-γ, cortisol, and androgens also upregulate the enzyme(s) which does this—even in the event of adequate NAD⁺/NADH.

He explains the increase in histamine strictly through reduced histamine elimination, but provides no solid line of reasoning to indicate this. Surely this is highly logical, and could be correct, but it would have been easy for him to also measure the excreted N¹-methylhistamine and N¹-methylimidazole acetic acid and compare that with the increase—which he hadn't. There could be other reasons for the increase in histamine.. .

'The present findings, together with earlier results showing that nicotinamide load increased plasma norepinephrine but decreased its methylated derivatives, suggest that excessive nicotinamide could inhibit the degradation of monoamine neurotransmitters presumably due to methyl-group pool depletion.' ―Tian​

Since the very best evidence of schizophrenic phenotype—in my opinion—all point to the behaviour being caused by an increase in histamine, I have to agree with Janelle that this makes no sense from an Abram Hoffer standpoint at first glance. But since I had previously assumed that niacin is effective in schizophrenia because it physically displaces histamine from binding sites, these results present no paradox as far as I'm concerned. Niacin causes a well-known flush yet so does histamine, and the two molecules are similar in size (and both have an N-containing ring).

[1] Fernstrom, J. "Effects of the diet on brain neurotransmitters." Nutrition Reviews (1974)​

 

[Travis]

@Travis @tyw Haidut et al, have you guys seen this?

Excess nicotinamide increases plasma serotonin and histamine levels. - PubMed - NCBI

If so, what is your take regarding this study/outcome?

You know, I started thinking when smoking a cigarette that the increase in serotonin isn't something to be particularly concerned about since plasma serotonin is normally excluded from the brain. And moreover: since trypophan is degraded in the process of becoming serotonin in the liver, each precursor molecule modified would necessarily become unavailable for brain uptake: Serum tryptophan is the precursor for brain serotonin; plasma serotonin is not. This would mean that taking niacin would be expected to have little-to-no effect on brain serotonin since the amount of tryptophan which had become serotonin would be largely offset by the amount of tryptophan spared by niacin; these two are in fact the very same tryptophan molecules that can become things like picolinate, niacin, and serotonin in an either/or selection process. The tryptophan pool could stay at more-or-less the same concentration regardless of what its peripheral metabolites happen to be.

And I had started to think that histamine had increased simply on account of niacin had interfered with its degratory pathways—the Tian Explanation (above)—perhaps even simply by stealing the methyl group needed; I have found a better way to explain the apparent Hoffer Paradox:

Niacin and histamine do have opposite charges, so one would be hesitant to assume that they directly interact—but it's not necessarily to assume that they do.

These two molecules are actually quite different and even have opposite charges.

The molecule that niacin has more in common with is the amino acid histidine, which is actually the precursor for brain histamine—not plasma histamine.

These two molecules are more similar.. .

Since schizophrenia is more correlated with cerebrospinal fluid histamine than it is with any other neurotransmitter,⁽¹⁾ inhibiting brain uptake of histidine would seem most effective. I think the best explanation for how niacin reverses schizophrenic behaviour could lie in blood–brain histidine uptake kinetics, and how plasma niacin interferes with this. After all: schizophrenia appears to be caused by brain histamine (not plasma histamine) and there is only one precursor for all histamine found in the brain. Although brain mast cells could very well be the primary cause of the increased histamine synthesis rate, these too depend on the essential amino acid histidine for histamine production.

Histamine is merely decarboxylated histidine.

Could niacin interfere with this process somehow . . . either enzymatically or by inhibiting brain uptake?

[1] Prell, G. "Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms." Schizophrenia research (1995)
​

 

[Texon]

You know, I started thinking when smoking a cigarette that the increase in serotonin isn't something to be particularly concerned about since plasma serotonin is normally excluded from the brain. And moreover: since trypophan is degraded in the process of becoming serotonin in the liver, each precursor molecule modified would necessarily become unavailable for brain uptake: Serum tryptophan is the precursor for brain serotonin; plasma serotonin is not. This would mean that taking niacin would be expected to have little-to-no effect on brain serotonin since the amount of tryptophan which had become serotonin would be largely offset by the amount of tryptophan spared by niacin; these two are in fact the very same tryptophan molecules that can become things like picolinate, niacin, and serotonin in an either/or selection process. The tryptophan pool could stay at more-or-less the same concentration regardless of what its peripheral metabolites happen to be.

And I had started to think that histamine had increased simply on account of niacin had interfered with its degratory pathways—the Tian Explanation (above)—perhaps even simply by stealing the methyl group needed; I have found a better way to explain the apparent Hoffer Paradox:

Niacin and histamine do have opposite charges, so one would be hesitant to assume that they directly interact—but it's not necessarily to assume that they do.

View attachment 9134 These two molecules are actually quite different and even have opposite charges.

The molecule that niacin has more in common with is the amino acid histidine, which is actually the precursor for brain histamine—not plasma histamine.

View attachment 9135 These two molecules are more similar.. .

Since schizophrenia is more correlated with cerebrospinal fluid histamine than it is with any other neurotransmitter,⁽¹⁾ inhibiting brain uptake of histidine would seem most effective. I think the best explanation for how niacin reverses schizophrenic behaviour could lie in blood–brain histidine uptake kinetics, and how plasma niacin interferes with this. After all: schizophrenia appears to be caused by brain histamine (not plasma histamine) and there is only one precursor for all histamine found in the brain. Although brain mast cells could very well be the primary cause of the increased histamine synthesis rate, these too depend on the essential amino acid histidine for histamine production.

View attachment 9137 Histamine is merely decarboxylated histidine.

Could niacin interfere with this process somehow . . . either enzymatically or by inhibiting brain uptake?

[1] Prell, G. "Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms." Schizophrenia research (1995)
​

The Hoffer Paradox....I love it. I think you may have coined a new term my friend. @haidut I tagged you here since we had a recent exchange about this above.

As so often is the case, there seems to be a lot more going on here than it may appear at first glance.

 

[Travis]

The Hoffer Paradox....I love it. I think you may have coined a new term my friend. @haidut I tagged you here since we had a recent exchange about this above.

As so often is the case, there seems to be a lot more going on here than it may appear at first glance.

Even histidine brain uptake itself is interesting because it's usually listed under the 'charged amino acids,' and as such not assumed to be freely-transportable into the brain. However, this classification arises based-on its charge at pH 7.0 and the bloodstream has a pH of around 7.4. Histidine is the only real diprotic amino acid in this pH range, with its ring nitrogen having either a hydrogen or not. At physiological pH, more histidine is found in the neutral state than is found at pH 7.0.

All of the classic tryptophan competitors are neutral: leucine, isoleucine, phenylalanine, tyrosine, and valine all have no net charge at physiological pH. A non-charged molecule is necessarily less polar, hence more water-soluble, and hence more lipid-soluble than its charged analogue. I do think thing that MSG fear-mongering is a bit overblown since glutamate doesn't enter the brain very readily. While it is true that this is a dietary amino acid and a brain neurotransmitter, it is also synthesized from glutarate [sic]—a product of the citric acid cycle. Thus, the vast majority of brain glutamate is most likely synthesized within the brain from glucose.

Monosodium glutamate fear-mongering shifts the blame away from the domestically-produced food toxins towards a relatively harmless foreign scapegoat. Done by domestic multi-billion dollar corporations, executed by media outlets, and then amplified by the innocently-naïve, the MSG fear-campaign can reach an intensity bordering on the anti-Jap propaganda of the mid-1930s.
​

I tried to search for any indication of niacin competing with histidine for brain uptake but found none, absolutely zero, but I do remember reading a study before using radio-lableled niacin showing rapid brain uptake; quite a bit of niacin had been found as brain NADH within 30 minutes after injection. Although there are dozens of theories of schizophrenia, I am convinced that it is primarily elevated brain histamine. Perhaps one of these days I'll buy L-histidine and see what happens.. .

 

[am00]

Yes, that too. Good point.

If my serotonin receptors are decreased and autoreceptor is expectedly desentisized from SSRI use (libido is low, so are sex hormones), could it be that my dopamine is still normal, since any dopaminergic sup gives me anxiety? What do you recommend for resensitizing serotonin receptors and increasing their number?

 

[Jackrabbit]

If my serotonin receptors are decreased and autoreceptor is expectedly desentisized from SSRI use (libido is low, so are sex hormones), could it be that my dopamine is still normal, since any dopaminergic sup gives me anxiety? What do you recommend for resensitizing serotonin receptors and increasing their number?

A 5ht-2a receptor antagonist

 

[golder]

@haidut, is this still available for lab research? I can't see it on thewebsite - if not, why was it removed?

 

[haidut]

@haidut, is this still available for lab research? I can't see it on thewebsite - if not, why was it removed?

No, it was removed more than 3 years ago. Peat said he does not like it and it does contain fluorine, which makes it potentially hepatotoxic.

 

[golder]

Thanks for letting me know. Admire your honesty/credibility.

 

[Momado965]

The studies I saw (and posted some of them above) used it for up to a year without any ill effect. Unlike clonidine, which ha very unpleasant withdrawal/rebound effects, I am not aware of the serotonin antagonists like cypro and ritanserin having such effect. Like any receptor agonist/antagonist, chronic use would change sensitivity to serotonin dopamine, but that would happen anyways with endogenous serotonin and dopamine rising/falling. So, in theory at least, a person taking a serotonin antagonist would not be very different from a person who is naturally stress free and in good metabolic health - i.e. as a result of the lower serotonin synthesis the serotonin "receptors" density increases and the person becomes more sensitive to serotonin as a result. Whether that is good or bad in the long run is not a normative question - i.e. the answer is "it depends" on what you are after. I don't see a need for high serotonin so I think having low serotonin and high serotonin sensitivity is a good thing. Other people may feel differently.

Can the low serotonin be maintained even after stopping ritanserin?

 

[Wolf]

Even histidine brain uptake itself is interesting because it's usually listed under the 'charged amino acids,' and as such not assumed to be freely-transportable into the brain. However, this classification arises based-on its charge at pH 7.0 and the bloodstream has a pH of around 7.4. Histidine is the only real diprotic amino acid in this pH range, with its ring nitrogen having either a hydrogen or not. At physiological pH, more histidine is found in the neutral state than is found at pH 7.0.

All of the classic tryptophan competitors are neutral: leucine, isoleucine, phenylalanine, tyrosine, and valine all have no net charge at physiological pH. A non-charged molecule is necessarily less polar, hence more water-soluble, and hence more lipid-soluble than its charged analogue. I do think thing that MSG fear-mongering is a bit overblown since glutamate doesn't enter the brain very readily. While it is true that this is a dietary amino acid and a brain neurotransmitter, it is also synthesized from glutarate [sic]—a product of the citric acid cycle. Thus, the vast majority of brain glutamate is most likely synthesized within the brain from glucose.

Monosodium glutamate fear-mongering shifts the blame away from the domestically-produced food toxins towards a relatively harmless foreign scapegoat. Done by domestic multi-billion dollar corporations, executed by media outlets, and then amplified by the innocently-naïve, the MSG fear-campaign can reach an intensity bordering on the anti-Jap propaganda of the mid-1930s.
​

I tried to search for any indication of niacin competing with histidine for brain uptake but found none, absolutely zero, but I do remember reading a study before using radio-lableled niacin showing rapid brain uptake; quite a bit of niacin had been found as brain NADH within 30 minutes after injection. Although there are dozens of theories of schizophrenia, I am convinced that it is primarily elevated brain histamine. Perhaps one of these days I'll buy L-histidine and see what happens.. .

I had a rat that went down the histidine, egcg, and maoi b route. Fun times.

 

[Mauritio]

Anybody know where to get ritanserin in europe nowadays ?

 

[AinmAnseo]

What is the product most like ritanserin that idealabs now offers?
Metergoline?
Diamant?