Dihydromyricetin

[Zeta]

Hi everyone,

 

I enjoy drinking wine, but am worried about the consequences on brain health (esp. because dementia runs in my family, and I'm a likely APOE-epsilon 4 carrier).

 

I just came across an article about dihydromyricetin, which astonished me:

 

http://www.wired.com/2014/05/hangover-cure/

 

And another:

 

http://www.redorbit.com/news/technology/1112757967/research-conducted-at-ucla-confirms-blucetin-as-first-scientifically-validated/

 

Google it and you'll find many more.

 

Not a lot of peer-reviewed work has been published on it, but (despite the conflict of interest) the following does look promising:

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292407/

 

If you look at "cited by" you'll see more articles.

 

 

Does anyone here have further information about dihydromyricetin? I don't know enough about how ethanol harms to the brain to know whether the effects on GABA receptors would militate against damage, or would rather simply counteract some of the other effects of alcohol.

 

Thanks,

Z

[Michael R]

I strongly urge you to completely disregard this.

 

They have an hypothesis about what causes alcohol dependence and withdrawal syndrome (which, note, is NOT hangover, despite the article and even the researchers talking about it), and they have a molecule that seems to confirm that hypothesis in alcohol-dependent rats. Maybe, maybe this will one day be a treatment to help people recover from alcoholism, or reduce their likelihood of becoming dependent, if the same can be shown in humans (tho' I would fear moral hazard in either case). But that tells you nothing at all, at all about dementia.

 

The proper guard against dementia from alcoholism is moderation; consumption of wine rather than spirits or beer; and making sure you get plenty of thiamin in your diet (secondary thiamin deficiency being the mechanism of some forms of alcohol-driven dementia).

[Zeta]

 

They have an hypothesis about what causes alcohol dependence and withdrawal syndrome (which, note, is NOT hangover, despite the article and even the researchers talking about it), and they have a molecule that seems to confirm that hypothesis in alcohol-dependent rats.

 

Well, there are other hypotheses, and, far more importantly here (whether or not they emphasize it in their published work) other findings, like the blocking of (at least some aspects of) intoxication in rodents. ("Dihydromyricetin (DHM, 1 mg/kg, i.p. injection) [...] counteracted acute alcohol (EtOH) intoxication.")

 

 

Maybe, maybe this will one day be a treatment to help people recover from alcoholism, or reduce their likelihood of becoming dependent, if the same can be shown in humans (tho' I would fear moral hazard in either case). But that tells you nothing at all, at all about dementia.

 

Depends on what you mean by "tell", but "nothing at all, at all" seems far too absolute.

 

I'm simply trying to speculate, not draw solid, empirically verified conclusions about human application, since that's obviously not possible.

 

If ethanol-induced brain damage is at least partly mediated through ethanol's alteration of GABA(A) receptors, it seems reasonable to speculate that DHM might reduce ethanol-induced brain harm, short-term and long-term.

 

Anything more than speculation isn't warranted of course. But if the risks of taking DHM are extremely low, the decision to take it when one wants to drink a little might be wise.

 

The proper guard against dementia from alcoholism is moderation; consumption of wine rather than spirits or beer; and making sure you get plenty of thiamin in your diet (secondary thiamin deficiency being the mechanism of some forms of alcohol-driven dementia).

 

Yes, thiamin is critical! Few people know that, oddly.

 

The question of dementia from alcoholISM is not quite the same as the question of dementia from non-alcoholic consumption of alcohol. My question is about the latter.

 

There are times when I might want a glass or two of wine, and I'm speculating that the harm possibly done by that (minimal, to be sure!) might be able to be mitigated by DHM.

[Michael R]

I strongly urge you to completely disregard this.

 

They have an hypothesis about what causes alcohol dependence and withdrawal syndrome... and they have a molecule that seems to confirm that hypothesis in alcohol-dependent rats. Maybe, maybe this will one day be a treatment to help people recover from alcoholism .... But that tells you nothing at all, at all about dementia.

Well, there are other hypotheses, and, far more importantly here (whether or not they emphasize it in their published work) other findings, like the blocking of (at least some aspects of) intoxication in rodents. ("Dihydromyricetin (DHM, 1 mg/kg, i.p. injection) [...] counteracted acute alcohol (EtOH) intoxication.")

 

The fact that there are other hypotheses is rather my point, as regards dependence. And their proposed mechanism makes sense in terms of at least some aspects of intoxication, too: many of the signs & symptoms of drunkenness are due to alcohol being a CNS depressant,

and GABA is the premier CNS depressant neurotransmitter (hence the benzodiazepines, and the misguided use of GABA supplements as sleep aids). DHM would, under their hypothesis, inhibit acute CNS depression by competitive inhibition of GABA signaling, and would delay and potentially alleviate dependence by providing an alternative, milder binder (cf. the hypotheses on genistein vs. breast cancer). But there's no reason to link that with alcohol-associated dementia AFAICS.

 

Depends on what you mean by "tell", but "nothing at all, at all" seems far too absolute.

 

I'm simply trying to speculate, not draw solid, empirically verified conclusions about human application, since that's obviously not possible.

What I'm saying is: they haven't suggested, and AFAICS their data don't povide any rational basis for speculating independently, that it might have an effect on alcohol-driven dementia. The neurotoxic effects of acute alcohol intoxication, and the long-term structural damage observed in cases of alcohol-asociated dementia (Wernicke-Korsakoff and non-) are quite well-documented, and I've never seen anyone associate the mechanisms of dependence generally or GABA receptor alterations specifically therewith, nor does my amateur neuroscientist draw even tentative associations therewith. See here and here. Indeed, as an 'exception that proves the rule,' the second paper I linked says briefly at one point "Other mechanisms that may influence alcohol-related neurotoxcity and cognitive dysfunction are free radical toxicity, acetaldehyde toxicity, modulation of the nicotinic acetylcholine receptor, serotonin receptor, dopamine receptor, opioid receptor, and gamma-aminobutyric acid (GABA) receptor, but additional studies are necessary to confirm these findings" -- but the paper cited for the potential involvement of GABA receptors, turns out to have nothing at all to do with long-term impairment of cognition or dementia (nor even do the authors speculate that it might), but rather is about the acute cognition-impairing effects of alcohol, which again makes perfect sense because of GABA's CNS depressant effects.

 

If ethanol-induced brain damage is at least partly mediated through ethanol's alteration of GABA(A) receptors, it seems reasonable to speculate that DHM might reduce ethanol-induced brain harm, short-term and long-term.

If you throw the kinds of alterations in GABA receptors that they speculate drive dependence in as 'brain damage/harm,' sure. But there's no reason to think that those changes would have anything to do with the brain damage/harm of alcohol-driven dementia.

 

Just this month, the authors reported that DHM reduces a range of brain, body, and behavioral abnormalities in a mouse model of foetal alcohol syndrome -- but the behavioral effects were on epileptic-type seizure vulnerability (consistent with an effect on GABA receptors), not on cognitive function (which wouldn't really be). That's argumentum ex silentio, of course, but it suggests that the authors aren't even thinking it's worthwhile to do cognitive testing based on their understanding of DHM's mechanism of action. And they're right ;) .

 

Anything more than speculation isn't warranted of course. But if the risks of taking DHM are extremely low, the decision to take it when one wants to drink a little might be wise.

Again, what I'm saying is: in this case there isn't even a rational warrant for speculation. And we know zilch about the safety of DHM in these pharmacologic doses: there isn't even a 2-y subchronic toxicity study in rats.

 

The question of dementia from alcoholISM is not quite the same as the question of dementia from non-alcoholic consumption of alcohol. My question is about the latter.

Yes -- and (sorry to beat a dead mouse) this paper is (potentially) relevant for alcoholISM, and not to dementia, whether in abusers or moderate users.

 

There are times when I might want a glass or two of wine, and I'm speculating that the harm possibly done by that (minimal, to be sure!) might be able to be mitigated by DHM.

Remember, the epidemiology is pretty clear that a glass or two of wine is actually protective against dementia, and there is mechanistic basis for thinking that this is a real causal association and not just a reflection of confounding with conscientiousness.

[Zeta]

Thanks for reply! It will take a few days for me to formulate a thorough response. One quick, important thing for now --

 

Remember, the epidemiology is pretty clear that a glass or two of wine is actually protective against dementia, and there is mechanistic basis for thinking that this is a real causal association and not just a reflection of confounding with conscientiousness.

 

1) As noted, I'm a likely APOE-epsilon-4 carrier, and 2) the evidence is quite pretty clear that alcohol does not have the same beneficial effects in epsilon-4 carriers. Some researchers think it might have positive effects, just less dramatic than those seen in non-carriers. These researchers, however, are in a shrinking minority. Most think either it has no beneficial effects at all (on dementia avoidance or cardiovascular pathologies), or that it's harmful -- even one glass/day. A somewhat out-of-date summary is here:

 

http://apoe4.info/MWiki/index.php?title=Alcohol_consumption

 

-Zeta

[Michael R]

Remember, the epidemiology is pretty clear that a glass or two of wine is actually protective against dementia, and there is mechanistic basis for thinking that this is a real causal association and not just a reflection of confounding with conscientiousness.

1) As noted, I'm a likely APOE-epsilon-4 carrier, and 2) the evidence is quite pretty clear that alcohol does not have the same beneficial effects in epsilon-4 carriers. Some researchers think it might have positive effects, just less dramatic than those seen in non-carriers. These researchers, however, are in a shrinking minority. Most think either it has no beneficial effects at all (on dementia avoidance or cardiovascular pathologies), or that it's harmful -- even one glass/day. A somewhat out-of-date summary is here:

 

http://apoe4.info/MWiki/index.php?title=Alcohol_consumption

I don't think that's an accurate summary of the linked source:

 

Might APOE status affect relevance of the research supporting this intervention?

 

(See above. Answer: Yes.)

 

Recent reviews:

 

PubMed ID:22396679 (free full text available)

 

PubMed ID:22396249

 

PubMed ID:21857787

 

PubMed ID:20617045

But if you look at those reviews, they suggest a very mixed picture, with ApoEε4 conferring either enhanced, diminished, or null effect on the protective effect of mild consumption, with carrier status possibly worsening heavy drinking in some studies:

 

In some studies, benefit [from mild alcohol consumption] was evident only in subjects carrying an APOEɛ4 allele, or an APOEɛ4 allele enhanced the protective effect [80,110]. In other studies, benefit was evident only in subjects lacking an APOEɛ4 allele, or an APOEɛ4 allele reduced the protective effect [82,109,112,115]. One study found no effect of APOEɛ4 genotype on risk reduction [114].

PubMed ID:20617045

Is there any common factor in the ratios that showed significantly worse cognition in drinkers?

The ratios of 7.07 for dementia from Anttila et al139 and 7.42 for dementia from Kivipelto et al159 were from subjects in Finland drinking frequently, often in binges, who also had the apolipoprotein E epsilon 4 (APOE epsilon4) allele. ... In summary, 13/23 ratios (57%) in the “worse” group were associated with either heavy drinking (12) or the APOE epsilon4 allele (1). The remaining ten ratios linking light, moderate, or unknown amounts of alcohol consumption with significantly increased risk of dementia or cognitive impairment represent only 2.2% (10/446) of the total. ...

 

Does the APOE epsilon4 allele alter the effect of alcohol on cognition?

The presence of the APOE epsilon4 allele appeared to eliminate the significantly reduced cognitive risk effect of moderate drinking, as seen for ɛ4 (0.89) and noɛ4 (0.70) in Figure 5. ..

 

In conclusion, although analysis found that the presence of APOE epsilon4 allele eliminated any significant “protective” effect of moderate ethanol on cognitive risk, a number of other studies have found an opposite effect and our results are based on a relatively small number of ratios from just ten studies, leaving this question unsettled.PMID: 21857787

The role of alcohol in cognition might be modified by the presence of the APOE ε4 allele (Carmelli et al., 1999; Dufouil et al., 2000; Virta et al., 2010), but the patterns of interaction suggested have seen different results (Stampfer et al., 2005; Ngandu et al., 2007). … [G]enetic susceptibility seems to modify the effect of alcohol on risk of dementia and predementia syndromes, with some studies suggesting that the APOE ε4 carrier status acts as a possible effect modifier for these associations (Panza et al., 2009). Nonetheless, the protective effects of light-to-moderate alcohol consumption against dementia and cognitive decline are more likely in the absence of an APOE ε4 allele (Panza et al., 2009). The effect of the APOE ε4 allele on dementia is suggested to attenuate with increasing age, which might partly explain the conflicting results concerning effect modification in studies on older cohorts (aged 65 years and older; Panza et al., 2009). One possible explanation could be that people with the ε4 allele have less effective neural repair mechanisms (Panza et al., 2009); and thus, they would be more susceptible to the deleterious effects of alcohol. It is also possible that it is a particular drinking pattern (i.e., binge drinking) that together with APOE ε4 carrier status forms a hazardous combination in some populations (Panza et al., 2009). However, what has yet to be investigated as a possible additional variable is whether there are any additional genetic variants, such as genes encoding enzymes involved in alcohol metabolism, that may also be involved.

PMID: 22396249

Only one of the cited reviews argues for carrier status conferring an increased risk from alcohol consumption without specifying they're talking about binge or heavy drinking, but (a) it barely mentions it, (B) it doesn't make any distinctions by quantity or pattern, and © it is arguing entirely from mechanistic speculation, with no reference to epidemiological evidence:

 

The apolipoprotein E (APOE) epsilon 4 allele provides a possible genetic explanation for susceptibility to alcohol-induced neurotoxicity. Research findings suggest that people with the allele have a less effective neural repair mechanism and, thus, are more susceptible to the deleterious effects of alcohol.

PubMed ID:22396679

I appreciate that in a person with high and unmodifiable background risk, "leaving this question unsettled" is rather ... er ... unsettling ;) , but taking a largely untested megadose dietary supplement based on mechanistic speculation (even a reasonable one, let alone one like this that has no prior plausibility) based on a risk that may or may not even exist is a very, very unsound response to that uncertainty.