10 replies to this topic

[opales]

Hi,

Since most here take stacks consisting of maybe dozens of supplement, I thought it might be uselful review some possible interactions . Because we don't really know all that well what these substance do in the body, we should start with some common interactions, like neurotransmitter activity or liver metabolism.

I actually got interested in the subject when I realized resveratrol, green tea and Rhodiola are all possible MAO-inhibitors. Obviously extensive MAO-inhibition has problems in and on itself (tyramine foods, serotonin syndrome etc.) but also interacting with other sbstances, for example melatonin appears to be contraindicted with MAO Inhibitors (because MAOs metabolize melatonin). I bet many here take large amounts of resveratrol, green tea and Rhodiola and melatonin everyday. Even if we are not going to do anything to avoid the possible interaction, I think it still would be good to at least be aware of it.

The liver enzymes interactions are a real pain in the ass to go through, has anyone ever tried make some analysis on that one?

Resveratrol and MAOs

1: Biochem Biophys Res Commun. 2006 Jun 2;344(2):688-95. Epub 2006 Apr 17.Click here to read  Links
    Inhibitory effects of cis- and trans-resveratrol on noradrenaline and 5-hydroxytryptamine uptake and on monoamine oxidase activity.

        * Yanez M,
        * Fraiz N,
        * Cano E,
        * Orallo F.

    Departamento de Farmacologia, Facultad de Farmacia, Universidad de Santiago de Compostela, Santiago de Compostela (La Coruna), Spain.

    This study investigated for the first time the potential effects of cis- and trans-resveratrol (c-RESV and t-RESV) on noradrenaline (NA) and 5-hydroxytryptamine (5-HT) uptake by synaptosomes from rat brain, on 5-HT uptake by human platelets, and on monoamine oxidase (MAO) isoform activity. Both c-RESV and t-RESV (5-200 microM) concentration-dependently inhibited the uptake of [3H]NA and [3H]5-HT by synaptosomes from rat brain and the uptake of [3H]5-HT by human platelets. In both experimental models, t-RESV was slightly more efficient than c-RESV. Furthermore, in synaptosomes from rat brain, the RESV isomers were less selective against [3H]5-HT uptake than the reference drug fluoxetine (0.1-30 microM). On the other hand, both c-RESV and t-RESV (5-200 microM) concentration-dependently inhibited the enzymatic activity of commercial (human recombinant) MAO isoform (MAO-A and MAO-B) activity, c-RESV being slightly less effective than t-RESV. In addition, both RESV isomers were slight but significantly more selective against MAO-A than against MAO-B. Since the principal groups of drugs used in the treatment of depressive disorders are NA/5-HT uptake or MAO inhibitors, under the assumption that the RESV isomers exhibit a similar behaviour in humans in vivo, our results suggest that these natural polyphenols may be of value as structural templates for the design and development of new antidepressant drugs with two important biochemical activities combined in the same chemical structure: NA/5-HT uptake and MAO inhibitory activity.

    PMID: 16631124 [PubMed - indexed for MEDLINE]

Green tea and MAOs

Indian J Exp Biol. 2006 Nov;44(11):913-7. Links
    Green tea [Camellia sinensis (L.) O. Kuntze] extract reverses the despair behaviour in reserpinised and diabetic mice.

        * Singal A,
        * Tirkey N,
        * Muragundla A,
        * Chopra K.

    Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160 014, India.

    Green tea (C. sinensis) extract (GTE) dose dependently produced reversal of despair in normal, reserpinised and diabetic mice, thereby demonstrating an antidepressant effect. Although the exact mechanism is yet to be explored, the possible inhibition of catechol-o-methyl transferase and monoamine oxidase enzymes may be responsible for antidepressant activity of GTE.

    PMID: 17205714 [PubMed - in process]

Rhodiola and MAOs
http://www.imminst.o...=post&id=149269

Extracts of R. rosea have been reported to influence
the levels and activities of biogenic monoamines, such
as serotonin, dopamine and norepinephrine, in the
cerebral cortex, brain stem and hypothalamus (Kurkin
and Zapesochnaya, 1986). It is believed that these
changes in monoamine levels are due to inhibition of
the activities of the enzymes responsible for monoamine
degradation (monoamine oxidase and catechol-Omethyltransferase),
and to facilitation of neurotransmitter
transport within the brain (Stancheva and
Mosharrof, 1987). Therefore we can postulate that
this antidepressant-like activity of RHO depends on
its ability to enhance the catecholaminergic system
(Burchfield, 1979; Lishmanov et al., 1987; Saratikov and
Krasnov, 2004; Panossian and Wagner, 2005).

[zoolander]

let's get a visual of this



I would like to see a little more information on the specific isoforms that the particular supplements inhibit. I have heard on many occasions to watch out for the tyramine effect with selegiline but it;s not something that one should be to concerned about. Selegiline is a selective MAO-B Inhibitor. MAO-B only metabolises 20% of the tyramine in the gut and 50% in the liver. The tyramine effect essentially results from high amounts of tyramine in the gut. So, even if you inhibit MAO-B in the gut with selegiline you still have 80% metabolism of the tyramine in the gut. So, by usingthis example I hope to stress the importance of knowing if the compound is a selective or non-selective MAOI and if so then does it inhibit A or B.

It is interesting that you mentioned resveratrol because one of the milder tyramine effects is headache. Red wine is known to cause headache in many people . It also recommended that people taking MOAI anti-depressants do not drink red wine. Do you think that this is because of the resveratrol in the red wine? If so, then I guess red wine from various regions would be more likely to result in the headaches as well due to their higher concentrations.

The seronin syndrome is a little more tricky.

Good info Olli. This sort of information would be useful when trying to work out the potential orgin of a problem. For example, if you consumed a diet consisting of tyramine containing foods and continually complained of headache or showed an increase in BP after consuming tyramine containing foods then you could eliminate the above supplements and see if it changes anything.

I might go off and read the above mentioned papers

[Pablo M]

Opales brings up an important point. I have heard the phrase "It's all natural, so it's completely safe" (an extremely fallacious statement) too many times. Natural products do have side effects and interactions. For example, I found some information that guggul inhibits a certain enzyme of the cytochrome p450s. The benefit to pharmaceuticals, despite whatever else the naysayers may say, is that they have been extensively studied so that interactions can be ascertained. Not so for the natural products.

In general, I try to follow Linus Pauling's recommendation that herbs be treated like drugs and only taken when necessary.

[zoolander]

this is very true Pablo......

Opales brings up an important point. I have heard the phrase "It's all natural, so it's completely safe" (an extremely fallacious statement) too many times. Natural products do have side effects and interactions. For example, I found some information that guggul inhibits a certain enzyme of the cytochrome p450s.

this is an interesting paper....

Basic Clin Pharmacol Toxicol. 2007 Jan;100(1):23-30.

    The Induction of CYP1A2, CYP2D6 and CYP3A4 by Six Trade Herbal Products in Cultured Primary Human Hepatocytes.
        * Hellum BH,
        * Hu Z,
        * Nilsen OG.

    Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

    The aim of this study was to evaluate the in vitro inductive potential of six commonly used trade herbal products on CYP1A2, CYP2D6 and CYP3A4 metabolic activities. Herbal components were extracted from the trade products in a way that ensured a composition equal to that present in the original product. Primary human hepatocytes and specific CYP substrates were used. Classic inducers were used as positive controls and herbal extracts were added in in vivo-relevant concentrations. Metabolites were determined by high performance liquid chromatography (HPLC). St. John's wort and common valerian were the strongest inducing herbs. In addition to induction of CYP3A4 by St. John's wort, common valerian and Ginkgo biloba increased the activity of CYP3A4 and 2D6 and CYP1A2 and 2D6, respectively. A general inhibitory potential was observed for horse chestnut, Echinacea purpurea and common sage. St. John's wort inhibited CYP3A4 metabolism at the highest applied concentration. Horse chestnut might be a herb with high inhibition potentials in vivo and should be explored further at lower concentrations. We show for the first time that G. biloba may exert opposite and biphasic effects on CYP1A2 and CYP2D6 metabolism. Induction of CYP1A2 and inhibition of CYP2D6 were found at low concentrations; the opposite was observed at high concentrations. CYP2D6 activity, regarded generally as non-inducible, was increased by exposure to common valerian (linear to dose) and G. biloba (highest concentration). An allosteric activation is suggested. From the data obtained, G. biloba, common valerian and St. John's wort are suggested as candidates for clinically significant CYP interactions in vivo.

[niner]

In general, I try to follow Linus Pauling's recommendation that herbs be treated like drugs and only taken when necessary.

Excellent advice.

p450 assays are not *that* hard to run. These days they are run earlier in the drug development process than they used to be, so lots of compounds get assayed. The average big pharma company probably has decent p450 inhibition data on ~5-10 thousand compounds, I'd guesstimate. Some companies have run high throughput p450 assays on a hundred thousand compounds, although these are not very accurate. A good supplement company could have samples assayed at a contract lab for a not insane amount of money, if they were so inclined. Perhaps they don't want to know the results...

[opales]

My impression is that almost everything will have an effect on the Cp450 (although the extent and specific enzymes affected appear to be key word here) or is metabolized by it, that's what I meant on being a pain to go through. In addition to the fact that liver metabolism is apparently highly variable between individual due to genetic variation in the alleles than encode the enzymes.

In fact, I think the mechanism of many anti-carcigonenics is believed (though controversial) to be the inhition of certain C450 enzymes, because the Cp450 enzymes convert procarcinogens to carcinogens, see for example (can't copy paste):
http://www.cron-web....ts-guide-4.html

FYI zoo, red wine contains subtantial amounts of TYRAMINE, this is the reason red wine is not recommended to people taking MAO inhibitors. But still red wine head ache combination of tyramine in red wine and MAO-inhibition of resveratrol (and possibly something else), interesting hypothesis. Note this is plausible as gut exposes to unmetabolized resveratrol, so this is not affected by the issue whether resveratrol metabolites are active or not. Although, the studies I have seen have been done on brain cells I am not sure if resveratrol has the same effect in the gut (I am obviously at the limits of my expertise here). If it does, and even the small amounts of resveratrol in wine are enough to inhibit MAO-A to cause headache, I wonder what happens when people supplement 100-fold as many here do?

BTW, selegiline does inhibit MAO-A at high doses.

Edited by opales, 17 January 2007 - 09:47 AM.

[zoolander]

FYI zoo, I am not sure if you are aware (not sure it is was implicitly part of your headache hypothesis) but I think red wine also contains subtantial amounts of TYRAMINE. So red wine head ache combination of tyramine in red wine and MAO-inhibition of resveratrol (and possibly something else), interesting hypothesis.

I thought that was what I said. I am having a bad communication week. That is what I meant to say.

[opales]

It also recommended that people taking MOAI anti-depressants do not drink red wine. Do you think that this is because of the resveratrol in the red wine?

I thought that was what I said. I am having a bad communication week. That is what I meant to say.

Well at first I assumed you knew about the tyramine in red wine but when I read your post again I got the impression you were speculating whether red wine is not recommended because of the resveratrol - MAO-connection, which is a very recent finding.

I wonder though if there are cases or studies in literature with "tyramine syndrome" due MAO-A inhibitors and red wine with red wine consumed less than would be expected to cause effects due tyramine (obvious explanation being that MAO-Inhibition was further enforced by resveratrol)?

[FunkOdyssey]

FYI zoo, red wine contains subtantial amounts of TYRAMINE, this is the reason red wine is not recommended to people taking MAO inhibitors. But still red wine head ache combination of tyramine in red wine and MAO-inhibition of resveratrol (and possibly something else), interesting hypothesis. Note this is plausible as gut exposes to unmetabolized resveratrol, so this is not affected by the issue whether resveratrol metabolites are active or not. Although, the studies I have seen have been done on brain cells I am not sure if resveratrol has the same effect in the gut (I am obviously at the limits of my expertise here). If it does, and even the small amounts of resveratrol in wine are enough to inhibit MAO-A to cause headache, I wonder what happens when people supplement 100-fold as many here do?

I can tell you what happens -- I've been getting wicked headaches after drinking just a glass or two of red wine, and one mother of a migraine on a particular evening where I drank five glasses. Although, I never drank red wine in the past so I don't know if I was already prone to get them from red wine (before supplementing with resveratrol).

Edited by FunkOdyssey, 17 January 2007 - 03:45 PM.

[Atropy]

Does anyone on this thread know of any nootropics that do not interact with Imipramine (Trycyclic anti-depressant)?

It seems like (from what I see on the internet) almost every nootropic and even non-nootropic health supplements interact with imipramine in some noticeable way.Its very frustrating.

[blood]

How about phosphatidyl serine, and the various types of choline like citicoline or GPC?

I find that high dose grape seed extract is very good for enhancing alertness, mental stamina, mood.