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aromatherapy in the treatment of Alzheimer's disease
Hey, Lane. Thanks for starting the thread."The alzheimer's in mice and other animals is not the same as the alzheimer's in human beings, nor are mice physiologically the equivalent of human beings. And yet, the differences are often not that great."That may be true for many disorders, but not for Alzheimer's. Mice do not naturally develop AD, they don't even naturally produce APP (the precursor to Abeta, which is the primary component in AD plaques.) The only way mice can be used in studies on AD is if they are genetically engineered to mimic some small part of the AD cascade. If I recall correctly, something like 200 different genes would have to be inserted into their genome to mimic everything that is known to be affected in humans, and of course, that isn't possible -- the mice never develop and grow. There are dozens of different strains that are used to study select parts of AD ... hypothetically.As for being able to treat Alzheimer's in genetically engineered mice ... I'm beginning to think there isn't anything that won't be found to be effective. To date, not a single drug that was developed using mice has made it through clinical trials. Researchers are beginning to doubt the utility of mice at all, for a number of different reasons. And they refer to genetically-engineered mice as having "mouseheimer's" since whatever they "have" is so different from AD.Which is why I warned you that I'm not fond of animal models when it comes to studying Alzheimer's.
While looking for that article, which I still haven't found, I ran across this one that cites a mouse study done by researchers who have developed a drug that reversed the damage to the olfactory bulb by AB plaques and returned the sense of smell within 2 weeks.
I, too, would welcome further studies on aromatherapy in the treatment of Alzheimer's disease (thank you for the posting advice, so that hopefully I can post future studies) . I have been begging for further studies for four years, but I either receive no response, a passive aggressive response, or a negative response. Those few researchers who recognize the potential of phenolic compounds in the treatment of Alzheimer's disease want to produce synthetic versions to patent them. The problem, I suppose, is that the natural compounds (methoxyphenols, for instance) appear not to need alteration to be effective.
I was grateful for the additional posts on studies with essential oils in healthy adults. It has led me to replace the use of Ylang Ylang with Peppermint essential oil. Having said that, though, there is no clinical proof the oils have the same effect on Alzheimer's patients as they have on non-Alzheimer's patients. I will therefore focus on the studies using essential oils in patients with dementia.
I am not in a position to evaluate whether one test for Alzheimer's is any more reliable than another test nor can I judge the credentials of the researchers nor whether their clinical trials were properly designed. It is true that Jimbo and colleagues did not use a placebo and I don't completely understand their methodology for factoring out caregivers' perspectives. However, I would be surprised if they would state that "all patients showed significant improvement in personal orientation related to cognitive function" if they were not confident in their methodology. The trial was a very short one and in my own personal experience (using one essential oil and inhalation from a bottle rather than four essential oils and a diffuser) it does take about a month to observe any notable difference. It is unfortunate that not more people were enrolled in the trial and a longer time frame was not used (at least four months), but hopefully Jimbo and colleagues are working on a more extensive trial.
The rapid decline in the placebo group in the Akhondzadeh study has been noted by other researchers. Some researchers think the improvement in the group receiving the essential oils was too great. They also wanted a description of the placebo used in both studies. Akhondzadeh's trial was of longer length than Jimbo's study and used what apparently are the more standard tests for cognitive function in Alzheimer's patients.
Again, here is my larger point: a person can say they don't accept animal studies, they can say they don't like case studies, they can point to flaws in methodology (all valid points), but they cannot say that essential oils have not shown effectiveness in various studies. Furthermore, once you understand the role of peroxynitrties in Alzheimer's disease and the role of several chemicals in various essential oils in not only neutralizing this toxin, but also in partially reversing its effects, then the results from the animal studies, case studies, and clinical trials make a great deal of sense. So, we can disagree about whether the evidence is weak or strong, but based on what we already now the need for more studies is urgent.
Lane, you've made a number of statements about what happens in human beings, e.g.:"Peroxynitrites cause dementia in a great variety of animals, including human beings because they lower the production of acetylcholine.""This happens with high levels of phospholipase C activity and the subsequent formation of amyloid plaques whether you are a mouse or a human being.""That is why peroxynitrite scavengers have not only worked in mouse models of Alzheimer's disease but also in clinical trials with human beings."Please provide references to studies done in human beings that support these statements. (Links, please -- many of our members don't know how to search the literature, so citations don't help them locate the papers to read for themselves what you're talking about. And a link to the full paper is best, not just an abstract in PubMed, because abstracts can be wildly misleading. I'm delighted to see you've learned how to post links. )I realize you've put a lot of time and effort into researching your hypothesis. However, it appears at first blush (and I readily admit I haven't read most of your posts, so if I'm wrong, please forgive me) that you haven't considered certain aspects of it. For example, for an antioxidant compound to counteract any negative effects of peroxynitrites, that compound has to make it to the intracellular site where the peroxynitrite is doing damage, and to make it there in sufficiently high concentrations to scavenge the peroxynitrite free radicals before the damage is done. Plenty of researchers are looking into free radical scavengers as potential treatments for, or protection against, Alzheimer's. So far, even though the pre-clinical data has been very promising, the clinical trial results have been underwhelming. Many researchers (most, as far as I know) believe that's because no single compound is going to make it through the body to the target cells and be taken up in high enough levels in all of the diverse types of target cells and into their diverse intracellular organelles to be affective. Focus has therefore shifted from treatment with a single type of antioxidant to treatments involving multiple compounds, each one carefully selected to target certain key structures within key types of brain cells.Take smell, for example. The odorant is not taken up by the human body and does not enter the brain to trigger a "smell" response. Instead, the odorant binds reversibly to biomacromolecules, called olfactory receptors, on the cilia on the outer surface of olfactory sensory neuron cells in the nose. The binding interaction triggers a chemical response cascade. http://en.wikipedia.org/wiki/Olfactory_receptorhttp://openwetware.org/wiki/BIO254:ORsI would also note that the sense of smell per se is not necessarily lost in the earlier stages of Alzheimer's in some patients. Instead, it appears to be the ability to identify certain odorants at more dilute concentrations that is lost. I.e., it is more of an agnosia phenomenon than a malfunction of the nose.In fact, very little of what we ingest or inhale makes it into brain cells. For example, the human body may not absorb what is ingested, may not digest it, and/or may quickly metabolize it and/or excrete it. And even most compounds that do enter the bloodstream intact cannot cross the blood-brain barrier.The larger point is not whether one "accepts" a given study or type of study, but whether one understands their limitations when it comes to extrapolating to what might be going on in the living human brain of a dementia patient.There are other problems with Akhondzadeh study data that would bother an experienced researcher. For example, the data is far too tightly clustered (the standard deviations are much too small) at each data point for such a tiny study involving dementia patients. Something about the studies simply wasn't done correctly, i.e., there are factors other than the essential oils affecting the outcome.It's not surprising that other critics have focused on the placebo that was used -- the data are much more what one would expect from an open-label study than a double-blind study. And it is difficult to imagine how one would design a suitable placebo for an aromatherapy study to be truly "blind". A pill that contains placebo, for example, will be exactly the same in appearance (color, size, shape, hardness, etc), smell, and taste as a pill that contains the drug.And yes, the experts at NIH not only can, but do, say that essential oils have not been shown to be effective. You have to understand clinical trials, experimental design, data analysis, etc etc etc before you can claim that the studies done to date on any treatment produced definitive proof.For example, the results of small studies on dementia patients can produce wildly skewed data, no matter how much care was taken in designing and executing the test protocols. Not one knowledgeable researcher will accept the apparent findings from a single large study, let alone a small one. I'll give you an example. There was a fairly large (183 participants), well-designed and -executed Phase II clinical trial on dimebon that produced wildly exciting results. The data appeared to indicate dimebon is actually disease-altering. Several additional, much larger, Phase III trials were launched, to much fanfare. The results from the first Phase III trial to be completed (involving 600 patients) were stunning: there was absolutely no difference between dimebon and placebo. For an interesting early analysis, see:http://www.ft.com/cms/s/2/089f09b2-264a-11df-aff3-
00144feabdc0.html#axzz1giwJL7uzNote in particular the comment, "... the medical community regularly sees smaller trials that originally show stellar results and fail in larger definitive trials." And the "smaller" trial here had, what, six times as many test subjects as one of the Akhondzadeh studies.The FDA requires at least two large, Phase III clinical trials that duplicate results before they'll consider approving a treatment. And the data have to be of very high caliber before two Phase IIIs are considered adequate.(And one little aside about plaque: many researchers believe the formation of plaque is actually a protective mechanism, and that one or more of the soluble forms of Abeta are likely to be the toxic species.)
The rosmarinic acid study is mildly interesting (sorry, mice don't do much for me ) but it's hard to see how it supports aromatherapy as a treatment for Alzheimer's. For one thing, the memory impairment was created by injecting Abeta(25-35) directly into the mouse brains. ("i.c.v." is "intracerebroventricular") This doesn't begin to mimic what happens in the diseased human brain. Moreover, the rosmarinic acid was administered by intraperitoneal inject, not by inhalation. That's going to have a major impact on distribution and metabolism. (One also wonders how volatile rosmarinic acid is -- it may not be possible to get a reasonable dose into the body by inhalation, even if its fate were to be the same as by injection.)Finally, the study was aimed at evaluating the potential for using rosmarinic acid to prevent the development of memory problems, not to treat Alzheimer's once it's already present. The possible mechanism of action of eugenol discussed in the Irie paper is the inhibition of Abeta-induced excessive calcium influx and thereby attenuation of excitotoxicity (i.e., behaving in a manner somewhat similar to Namenda). You may find this paper to be of interest, since it discusses much of the information that is known about eugenol:
Note this part of the discussion:"However, according to ourfindings, the action of clove extract on cognition isinversely dependent on its concentration. The negativerelationship involving the dose-dependant activity ofclove extract may be due to its hypnotic and anestheticeffect or to its vasodilator, hypotensive andbradycardial activity which may produce somedegree of motor dysfunction."The most important constituent of clove is eugenol.
It is an open question whether the chemicals in a smell can enter the brain even if the g protein coupled to the receptor is damaged. The argument for aromatherapy is the following: the chemicals in methoxyphenols partially reverse the damage done to g proteins coupled to olfactory receptors by peroxynitrites and then enter the hippocampus where they then partially reverse the oxidative damage done by peroxynitrites to another g protein coupled to a receptor involved in short-term memory (muscarinic acetylcholine). The methoxyphenols in several essential oils are highly concentrated and have a direct route to the hippocampus and for that reason I believe that they have a distinct advantage over other antioxidants. This is probably part of the problem with other phenolic compounds in mouse studies--they enter in large enough concentrations in mouse brains to make a difference, but not in great enough concentrations in human brains to make a difference. The study on rosmarinic acid was given just to indicate that some researchers believe that peroxynitrites are the cause of short-term memory impairment in Alzheimer's disease. Here are more direct mouse studies involving essential oils (and one on Ocimum sanctum since the very good article you posted makes reference to it). http://www.ncbi.nlm.nih.gov/pubmed/22070531
The first article notes that acute toxicity levels in Zataria multiflora Boiss. essential oil occur at much higher doses than the therapeutic dose in mice at least (the study does caution that more studies are necessary to confirm this as well as the potential effectiveness of Zataria multiflora Boiss. essential oil in Alzheimer's disease. This essential oil mainly contains carvacrol and thymol), At very high levels methoxyphenols such as carvacrol, thymol, and eugenol can become pro-oxidants rather than antioxidants, but it appears to be at very high levels. I wouldn't be sniffing from the bottle for minutes at a time or have the diffusers running for hours at a time without proper dilution (and you don't have to do either for the essential oils to be effective).
The point you make on eugenol and Namenda (memantine) is right on target. They both inhibit calcium influx and the release of glutamate. Eugenol, however is a better peroxynitrite scavenger than Namenda and therefore it is better able to limit the influx of calcium and the release of glutamate; which means that it is better at protecting neurons from cell death (peroxynitrites cause both problems by lowering levels of intracellular magnesium). http://www.ncbi.nlm.nih.gov/pubmed/1935602 As far as the Akhondzadeh's studies go, I see plenty of head scratching over them. People insist something else had to be at work, but my question is what. Maybe the essential oils were just that effective.
Many clinical trials on Alzheimer's disease have failed (and yet some of the drugs continue to be used). They have either dealt with a passing phase of the disease (high cholinesterase activity). The compounds cannot be delivered in high enough doses to be effective. The peroxynitrite scavengers employed are weak ones (Namenda and dimebon). The drugs don't effectively cross the blood-brain barrier. The problem being targeted is only a part of the problem of the overall disease (efforts to dissolve amyloid plaques). And on and on and on. There are reasons why all the trials have failed so far--they failed because the people conducting them did not understand the cause of the disease (sure amyloid plaques, hyperphosphorylated tau proteins, glutamate release, and calcium influx seem to be involved in some way, but how and why). Once you understand the disease, the likelihood of the trial succeeding increases substantially. Aromatherapy/essential oils have succeeded in treating Alzheimer's disease in mouse models, case studies, and small-scale clinical trials and if anyone has the money and courage to do it--they are very likely to work in large-scale clinical trials because they treat the cause of the disease--peroxynitrites.
It looks like there's a break in your link after "nature.com" that is making it redirect to the journal home page. Try posting your links in a separate line, rather than as part of a paragraph, and see if that helps.
I am very confused by your statements regarding the radical scavenging properties of Namenda as having anything to do with its efficacy in treating Alzheimer's. One of our members asked me for an explanation, which I posted:
There was never any mention of scavenging in any of the papers I read.
Could you please provide references that discuss the radical scavenging properties of Namenda as they affect its biological activity?
Let's start with the Namenda question first. The NMDA rececptor is gated by magnesium. If you lose most of the free intracellular magnesium, you increase the influx of calcium and the release of glutamate, which is probably the chief mechanism by which peroxynitrites contribute to the death of neurons. Compounds containing methyl groups such as dimebon and namenda appear to be (weak) peroxynitrite scavengers, although this is based on the peroxynitrite scavenging capabilities of other compounds containing methyl groups such as the following http://www.liebertonline.com/doi/abs/10.1089/jmf.2007.040.
The other questions that you raise are critical ones: do aromatic compounds enter the brain and can they reverse the damage done by peroxynitrites. Here is one study indicating that aromatic compounds do enter the brain (in mice at least) http://www.ncbi.nlm.nih.gov/pubmed/21639684 The notion that these compounds somehow get stuck in the nose flies in the face of all the positive and negative effects of aromatic compounds on human health (why is sniffing glue and breathing hydrocarbons harmful to the brains of human beings, for instance). Indeed aromatic compounds are the most likely compounds to enter the brain.
The idea that peroxnitrite scavengers can only scavenge peroxynitrites and not reverse part of their damage is also incorrect. G proteins are composed of sulfhydryl groups. Peroxynitrites remove hydrogen from them so that they cease to function properly. Some antioxidants act as hydrogen donors partailly restoring the function of g protein-coupled receptors. Here is one example of an antioxidant restoring the function of a g protein coupled receptor http://www.ncbi.nlm.nih.gov/pubmed/17191082
So to summarize, the compounds in essential oils do reach other parts of the brain and they can help restore the function of g proteins coupled to critical receptors.
I have a question from a previous post: the NIH says that aromatherapy is not effective in the treatment of Alzheimer's disease. On what basis does the NIH make that claim. I don't mind people saying that aromatherapy is ineffective in the treatment of Alzheimer's disease, but they need to present the same level of evidence against its use as the level of evidence presented by people who support its use. http://ezinearticles.com/?Debunking-the-Debunkers---
methyl groups such as dimebon and namenda appear to be (weak)
peroxynitrite scavengers, although this is based on the peroxynitrite
scavenging capabilities of other compounds containing methyl groups..."
In all the papers I've read on these two drugs, I have never
seen the slightest indication that their biological activity is, or even
might be, due to their being peroxynitrite scavengers.
Read the link I
provided to my post on the biological activity of Namenda for current
thought on its underlying mechanisms of function.
The current understanding of the biological activity of Namenda is based on a wide range of experiments, not on supposition.
"I have a question from a previous post: the NIH says that aromatherapy is not effective in the treatment of Alzheimer's disease. On what basis does the NIH make that claim."That is not what I said. I said, "And yes, the experts at NIH not only can, but do, say that essential oils have not been shown to be effective."There is a huge difference between saying that essential oils have not been shown to be effective, and saying that aromatherapy is not effective.For example, I provided you with a link to the Tangled Neuron website that other members had already given to you on the old forum, which cites an NIH analysis of lavender. It said, among other things, that there is "insufficient evidence to rate effectiveness for agitation in dementia. Study results have not agreed. In one study, nightly use of lavender oil in a bedside diffuser for 3 weeks reduced agitation in patients with various types of dementia. However, in another study, continuous use of lavender oil on a pad attached to a patient's shirt had no effect in a small group of patients with advanced dementia."I.e., they're saying exactly what I've been saying: the evidence for using essential oils in general, and aromatherapy in particular, is very weak.
"I don't mind people
saying that aromatherapy is ineffective in the treatment of Alzheimer's
disease, but they need to present the same level of evidence against its
use as the level of evidence presented by people who support its use. http://ezinearticles.com/?Debunking-the-Debunkers---The-True-Medicinal-Value-of-Aromatherapy&id=2584349 "
This article does not provide one single citation of a study in a peer-reviewed journal in support of its contentions. This is hardly compelling evidence.
You raise many issues, and I will try to respond to them. Dimethyl groups containing two CH3 (such as dimebon and namenda) appear to be effective scavengers of peroxynitrites ( ONOO-) because they contribute two hydrogen atoms and two electrons converting them into water and a nitrogen dioxide anion. This is not the traditional explanation for the action of these drugs, but the fact that methoxyphenols containing one CH3 group and one OH group (such as eugenol) also scavenge peroxynitrtites and in the process also lower the influx of calcium, it seems to me to be a reasonable possibility.
The article on aromatherapy does not provide full citations, but it does point readers to pubmed searches. You provided a previous link to a well-researched paper on the role of peroxynitrites in a variety of disease including Alzheimer's disease, ALS, multiple sclerosis, Parkinson's disease, some types of cancer, type 2 diabetes, some types of heart disease, and some types of stroke http://physrev.physiology.org/content/87/1/315.full.pdf. It is not surprising then that aromatherapy using essential oils high in methoxyphenols would be listed in preliminary studies on treating a whole suite of disease.
David Stewart is a registered aromatherapist. Anyone can look up his qualifications on the internet and make a judgment as to whether he is qualified to speak on these matters or not. Again, I don't endorse all of his ideas. His central argument (as far as we are concerned) is that the molecules in essential oils are very small and they are very concentrated and they enter the brain (whether by smell or some other mechanism). Again, this would explain why aromatic compounds can both help and hurt the human brain.
It is true that the cited abstract did not explain how the damage to the dopamine receptor was reversed. No matter what the mechanism, this shows that an antioxidant can at least partially restore the function of a g protein-coupled receptor (I think we can at least agree upon that). An agonist for the receptor was ineffective, but one antioxidant which scavenges peroxynitrites (tempol) was effective. http://www.ncbi.nlm.nih.gov/pubmed/18319733 Disruption of g protein coupled receptor occurs in Alzheimer's disease http://www.nature.com/nrn/journal/v12/n2/full/nrn2977.html and peroxnitrite-mediated damage is widespread in Alzheimer's disease.http://www.jneurosci.org/content/17/8/2653.full http://www.ncbi.nlm.nih.gov/pubmed/11562447You can make the connections or not.
I apologize for misquoting you. In regards to the use of essential oils in the treatment of behavioural issues, perhaps because of differences in research design or because not all behavioural issues are a result of the disease itself, the studies on the effects of essential oils and behavior in Alzheimer's disease are mixed, Does the NIH have anything to say about aromatherapy and/or essential oils in the treatment of symptoms which all Alzheimer's patients exhibit. Several essential oils are peroxynitrite scavengers and here are the essential oils that were effective in the previously discussed small-scale clinical trials: rosemary, lemon, lavender, and orange and tinctures with lemon balm and sage.
Here is some follow up information from last night. Peroxynitrites oxidize sulfhydryls
http://www.jbc.org/content/266/7/4244.full.pdf and by doing so they impair the function of g protein-coupled receptors http://cogprints.org/4095/1/Cys_Paper.pdf Peroxynitrite scavengers are also reducing agents (they add hydrogen back to sulfhydryls) thereby partially restoring the function of g protein-coupled receptors. These scavengers are thus not only antioxidants, they are also "reverse oxidants." Essential oils because they are small molecules and because they are highly concentrated can partially reverse the damage caused by peroxynitrites in Alzheimer's disease. Essential oils high in methoxyphenols and limonene (in citrus-based essential oils) appear to be the best reducing agents.
Here in one place is the evidence that peroxynitrite scavengers can partially restore the function of g protein-coupled receptors involved in short-term memory, smell, mood, sleep, social recognition, and behavior (in some cases) in human beings.
There is more than enough evidence to warrant a larger-scale clinical trial using aromatherapy to treat Alzheimer's disease. This should be done soon, despite the fact that very few people are going to make any money out of this form of treatment.
Small lipophilic compounds can cross the blood-brain barrier http://pubs.acs.org/subscribe/journals/mdd/v05/i06/html/06filmore.html#auth
and essential oils contain small lipophilic compounds.
It is interesting that many of the better peroxynitrite scavengers (cinnamon, clove, peppermint, rosemary, and sage) are potentially the most toxic, but also the least lipophilic. Maybe this is why at apparently effective doses, they appear not to be toxic to the brain.
The one out standing question now is do essential oils reach g protein-coupled receptors in high enough concentrations to reverse the peroxyynitrite caused oxidation of g protein-coupled receptors (and/or g proteins) in the human brain. I don't think anyone has the direct evidence for this yet. That is why larger-scale clinical trials with aromatherapy in the treatment of Alzheimer's disease are so crucial.