The Placebo Effect, Antioxidants and Neurochemistry
For some reason, the placebo effect is treated as if it is magic rather than science. If it is understood properly, it is a useful technique and its limitations can also be recognized - likewise, it is important to know when it could be affecting a patient unintentionally, to differentiate when the antioxidant effect is augmenting medical treatment from when something else medically real in the form of treatment or lifestyle changes might be successfully improving the patient's health status instead.
One example is blood pressure medications. It has been known since 1970 that calcium channel blockers can cure certain types of mental illness, and since then it has been found that calcium channel blockers, beta blockers, ACE inhibitors and ARBs can affect mental illness positively or negatively, depending upon the cause of that patient's mental illness. Anyone starting any of these medications should have their psychiatric team notified so they will look for changes to see if it's a benefit or detriment. If a person doesn't have a psychiatric team, they should be told to get a therapist who can monitor the changes before they start the blood pressure medication. However, this doesn't seem to happen.
Fragrances go directly to the scent perception part of the brain without the filters which sound and sight have. (Balance might go directly as scent does, despite being technically touch; also, part of taste is scent.) That allows it to causes direct changes. Through the personality, favorite colors and disliked colors can affect emotional changes, which then affect the brain through the shifting of emotions as the shifting of neurotransmitters. If not from association, preferences of colors might come from the benefit of transitions in the particular neurotransmitters which they induce - so, an either-way street.
Faith in God, especially for people who have a personal relationship with their deity, is something someone can carry with them all the time and continue to believe in, creating a constant increase in antioxidants. I will allow the atheist and true believers to argue God's side of it or not, but the faith itself is healing by reducing stress via reducing emotions which would reduce antioxidant levels, and also increasing antioxidant levels at the same time. The mix is idiosyncratic, probably different from each person to the next. But the effect is real, depending on the strength of that person's faith.
Because faith and belief and enjoyment all filter through the personality before they reach the brain, one person's antioxidant will be another person's stresses, increasing the body sensitivity to free radicals and neurotoxins.
However, when the doctor is not the correct specialty, when the condition is not clear, or if medical research has not gotten far enough to correctly diagnose or address their problem, a doctor may be unable to help except through antioxidants by giving emotional support, and by trying to figure out where to send the patient which might more appropriately address the actual cause his or her problem.
Nutritional deficiencies make people emotionally needy. The antioxidant effect improve their health by protecting their cells from damage, and reducing or even eliminating the nutritional deficiency for the duration. The doctor becomes the medication in these cases, but it makes it difficult both to diagnose, if lab tests are drawn afterwards, unless intracellular nutrients are tested, and difficult to explain to the pbeneficthat the reason going to the doctor is beneficial may not have to do with actual medicine. Some patients can become addicted to the emotional support of their doctor, but should be getting treatment for their physical condition, which may not be diagnosable or maybe for a different specialty.
This mechanism may be behind some hysterics being diagnosed with hypochondria incorrectly, when mineral lab tests show normal precisely because of the stress of which hysterics are symptomatic.
A web site by a patient with a non-Wilson's disease copper storage mutation warned that mindfulness and meditation would be necessary to detoxify from copper, because under stress the excess hides in certain organs in the body and does not present itself so that it is available to be removed. If a patient has distinct differences in their condition waking versus asleep, meditation (which simulates sleep for some purposes) during lab tests, if they can do it well, might show interesting and potentially useful results.
Likewise, the antioxidant effect of a caring doctor and kindly phlebotomist might have a beneficial effect which is temporary, yet could cause false results on nutrient lab tests. This is why the cortisol lab test using first morning saliva is prefered over blood tests.
(Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis, by James J DiNicolantonio, James H O’Keefe, and William Wilson; Open Heart. 2018; 5(1): e000668corr1. Published online 2018 Apr 5. doi: 10.1136/openhrt-2017-000668corr1; PMCID: PMC5888441; PMID: 29634047)
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888441/)
It is likewise important, for the trust and self-esteem of the patient, to avoid decreasing their antioxidant levels by attributing to placebo effect something that is real. Because the negative or anti-placebo effect of dismissal of a patient's very real experience, whether correctly interpreted by the patient or not, does damage through reduced antioxidant levels, and the mandate of a doctor is: First, do no harm.
---------
Magnesium and clotting, regarding post-stroke depression:
Effect of magnesium on fibrin formation from lower molecular weight (LMW) fibrinogen
https://pubmed.ncbi.nlm.nih.gov/11153893/
Lipinski B, Lipinska I. Effect of magnesium on fibrin formation from lower molecular weight (LMW) fibrinogen. Magnes Res. 2000;13(4):233-237.
---
References regarding magnesium and depression:
From: Aging and Disease
JKL International LLC
Association between Serum Magnesium Levels and Depression in Stroke Patients
Aging Dis. 2016 Dec; 7(6): 687–690.
Published online 2016 Dec 1. doi: 10.14336/AD.2016.0402
PMCID: PMC5198859
PMID: 28053818
Yingying Gu, Kai Zhao, Xiaoqian Luan, Zhihua Liu, Yan Cai, Qiongzhang Wang, Beilei Zhu,* and Jincai He*
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198859/
---
Magnesium and major depression
Eby GA, Eby KL, Murk H.
https://www.ncbi.nlm.nih.gov/books/NBK507265/#_NBK507265_pubdet_
---
Role of magnesium supplementation in the treatment of depression: A randomized clinical trial
PLoS One. 2017; 12(6): e0180067.
Published online 2017 Jun 27. doi: 10.1371/journal.pone.0180067
PMCID: PMC5487054
PMID: 28654669
Emily K. Tarleton,#1,* Benjamin Littenberg,#1,2 Charles D. MacLean,1,2,‡ Amanda G. Kennedy,1,2,‡ and Christopher Daley3,‡
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487054/
---
Case Reports
Rapid recovery from major depression using magnesium treatment
George A Eby et al. Med Hypotheses. 2006.
Eby GA, Eby KL. Rapid recovery from major depression using magnesium treatment. Med Hypotheses. 2006;67(2):362-370. doi:10.1016/j.mehy.2006.01.047
https://pubmed.ncbi.nlm.nih.gov/16542786/
---
Magnesium for treatment-resistant depression: a review and hypothesis.
Eby GA 3rd, et al. Med Hypotheses. 2010. PMID: 19944540 Review.
Eby GA 3rd, Eby KL. Magnesium for treatment-resistant depression: a review and hypothesis. Med Hypotheses. 2010;74(4):649-660. doi:10.1016/j.mehy.2009.10.051
---
Effects of Magnesium Supplementation on Unipolar Depression: A Placebo-Controlled Study and Review of the Importance of Dosing and Magnesium Status in the Therapeutic Response
Beata Ryszewska-Pokraśniewicz, Anna Mach, [...], and Maria Radziwoń-Zaleska
Nutrients. 2018 Aug; 10(8): 1014.
Published online 2018 Aug 3. doi: 10.3390/nu10081014
PMCID: PMC6115747
PMID: 30081500
Beata Ryszewska-Pokraśniewicz,1 Anna Mach,2,* Michał Skalski,2 Piotr Januszko,2 Zbigniew M. Wawrzyniak,3 Ewa Poleszak,4 Gabriel Nowak,5,† Andrzej Pilc,5 and Maria Radziwoń-Zaleska2,†
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115747/
---
Review
Magnesium in depression
Anna Serefko et al. Pharmacol Rep. 2013.
Pharmacol Rep. 2013;65(3):547-54.
doi: 10.1016/s1734-1140(13)71032-6.
Authors
Anna Serefko 1, Aleksandra Szopa, Piotr Wlaź, Gabriel Nowak, Maria Radziwoń-Zaleska, Michał Skalski, Ewa Poleszak
PMID: 23950577
DOI: 10.1016/s1734-1140(13)71032-6
Serefko A, Szopa A, Wlaź P, et al. Magnesium in depression. Pharmacol Rep. 2013;65(3):547-554. doi:10.1016/s1734-1140(13)71032-6
https://pubmed.ncbi.nlm.nih.gov/23950577/
---
Magnesium and depression
Anna Serefko et al. Magnes Res. 2016.
Serefko A, Szopa A, Poleszak E. Magnesium and depression. Magnes Res. 2016;29(3):112-119. doi:10.1684/mrh.2016.0407
https://pubmed.ncbi.nlm.nih.gov/27910808/
When people believe something will help or harm them, it affects their antioxidant levels. So a sympathetic phlebotomist could affect lab results by increasing antioxidant levels. This sort of improvement is often temporary, only lasting as long as the belief or sympathy does. However, if used intentionally to give the patient the energy to fix a practical issue, such as in an intervention, or to work to work through an emotional problem, the results can be long-lasting, even if the antioxidant level returns to normal.
Of course, something which lowers their antioxidant levels, if the patient cannot forget about it, can do a longer-lasting harm. A memory might play over and over again consciously, or subconsciously, running into similarities might increase stress. An example is a patient having emotional problems at the same time of the year as when someone close to them has died, without realizing that that is the cause.
But when a patient doesn't really believe that a medication or treatment is going to help or harm, then it is important for the doctor to look for a real cause of a health change - either a benefit or a damage.
One example is blood pressure medications. It has been known since 1970 that calcium channel blockers can cure certain types of mental illness, and since then it has been found that calcium channel blockers, beta blockers, ACE inhibitors and ARBs can affect mental illness positively or negatively, depending upon the cause of that patient's mental illness. Anyone starting any of these medications should have their psychiatric team notified so they will look for changes to see if it's a benefit or detriment. If a person doesn't have a psychiatric team, they should be told to get a therapist who can monitor the changes before they start the blood pressure medication. However, this doesn't seem to happen.
Another example would be aromatherapy. It is generally treated as if it works via the emotions, as if it is some sort of magical thing, which is why doctors don't treat it very seriously. The fact that it affects one person strongly, and doesn't affect another person nearly as much makes it difficult to use, but there is a reason for everything. when it is taken seriously, it is treated as if it affects the person psychologically, as an antioxidant inducer, and that is probably part of how it works. But anything that affect emotions changes the neurotransmitters. If a person has a nutritional deficiency or excess, such as copper, zinc or iron, a scent which reduces or increases dopamine or adrenaline can reduce or increase the use of those nutrients.
Zinc is a copper antagonists, and excess copper and iron can be gotten rid of by creating adrenaline. On the other hand, reducing adrenaline reduces copper and iron deficiencies by reducing waste. The aromatherapy or other treatment which is most beneficial would depend upon if one has an excess or deficiency.
Fragrances go directly to the scent perception part of the brain without the filters which sound and sight have. (Balance might go directly as scent does, despite being technically touch; also, part of taste is scent.) That allows it to causes direct changes. Through the personality, favorite colors and disliked colors can affect emotional changes, which then affect the brain through the shifting of emotions as the shifting of neurotransmitters. If not from association, preferences of colors might come from the benefit of transitions in the particular neurotransmitters which they induce - so, an either-way street.
Faith in God, especially for people who have a personal relationship with their deity, is something someone can carry with them all the time and continue to believe in, creating a constant increase in antioxidants. I will allow the atheist and true believers to argue God's side of it or not, but the faith itself is healing by reducing stress via reducing emotions which would reduce antioxidant levels, and also increasing antioxidant levels at the same time. The mix is idiosyncratic, probably different from each person to the next. But the effect is real, depending on the strength of that person's faith.
Because faith and belief and enjoyment all filter through the personality before they reach the brain, one person's antioxidant will be another person's stresses, increasing the body sensitivity to free radicals and neurotoxins.
It is important to differentiate when the patient is looking for increased antioxidant levels, aka looking for emotional support, instead of actual care, even if actual care is their stated purpose and indeed needed.. Different patients may go about it differently, which may confuse issues. That doesn't mean that they don't also need care, and need to be guided toward it. They may act inappropriately if they are trying to get rid of neurotoxins such as testosterone, the reason why some people who start to get dementia become more sexual without waiting to make sure that it is desired, or looking to use free radical copper and iron to create adrenaline, which might look as emotional venting, being manic, being judgmental, being afraid, or any number of other seemingly negative emotions and actions, unrelated to treatment.
Any of those might be strong enough needs that they can interfere with the patient actually trying to get the effect of medical treatment which, hopefully, will help them, and which again, hopefully, is what they came in for.
However, when the doctor is not the correct specialty, when the condition is not clear, or if medical research has not gotten far enough to correctly diagnose or address their problem, a doctor may be unable to help except through antioxidants by giving emotional support, and by trying to figure out where to send the patient which might more appropriately address the actual cause his or her problem.
There's a page on this site describing how nutritional deficiencies can cause mental illness, focused primarily on deficiencies from medications, other possible causes.
Nutritional deficiencies make people emotionally needy. The antioxidant effect improve their health by protecting their cells from damage, and reducing or even eliminating the nutritional deficiency for the duration. The doctor becomes the medication in these cases, but it makes it difficult both to diagnose, if lab tests are drawn afterwards, unless intracellular nutrients are tested, and difficult to explain to the pbeneficthat the reason going to the doctor is beneficial may not have to do with actual medicine. Some patients can become addicted to the emotional support of their doctor, but should be getting treatment for their physical condition, which may not be diagnosable or maybe for a different specialty.
If your patient is taking Depakote and has a combination of an iron deficiency, a folic acid deficiency, and an l-carnitine deficiency, those need to be addressed. All three (and more of the deficiencies recognized by pharmacists as caused by Valproic Acid) can cause, or cause an increase in, mental illness symptoms. As the patients' bodies get demanding and needy, the patients act the same way with their doctors, and other people. That does not mean that they need to take lithium, and balance their folic acid deficiency with a zinc deficiency so that both are equally low. It means that they need the nutritional deficiencies treated, and other medications added on once these deficiencies have been addressed, if required.
(See Replenish nutrients depleted: Valproic Acid at https://wa.kaiserpermanente.org/kbase/topic.jhtml?docId=hn-1535009 - and St. Lukes and other hospitals and clinics have the same information, seemingly from the same database. Pharmacists could and should be but are not teaching classes to doctors about this, as it seems not to have been in most doctors' curriculums.)
Unfortunately, bodies learn to adapt. Also, cortisol causes demineralization of amino acids, in an effort to optimize the blood so that, under the adrenaline that causes the increase in cortisol, the person can "fight that Cave Bear," the cave bear which hasn't existed in ages, but to which adrenaline is built to respond. In this case, the patient may have a fear of needles, may be stressed because of the nutritional deficiency itself, or because of unsuccessful results in the past, and the optimized blood will show normal, therefore lying to the doctor.
This mechanism may be behind some hysterics being diagnosed with hypochondria incorrectly, when mineral lab tests show normal precisely because of the stress of which hysterics are symptomatic.
A web site by a patient with a non-Wilson's disease copper storage mutation warned that mindfulness and meditation would be necessary to detoxify from copper, because under stress the excess hides in certain organs in the body and does not present itself so that it is available to be removed. If a patient has distinct differences in their condition waking versus asleep, meditation (which simulates sleep for some purposes) during lab tests, if they can do it well, might show interesting and potentially useful results.
Likewise, the antioxidant effect of a caring doctor and kindly phlebotomist might have a beneficial effect which is temporary, yet could cause false results on nutrient lab tests. This is why the cortisol lab test using first morning saliva is prefered over blood tests.
The study below on magnesium (which includes a study that was a study of over a hundred and sixty studies) includes both that lab tests often do not show out of range with magnesium deficiencies (and some alternative, more effective ways of testing), and that magnesium deficiencies can be caused by medications and many other causes.
(Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis, by James J DiNicolantonio, James H O’Keefe, and William Wilson; Open Heart. 2018; 5(1): e000668corr1. Published online 2018 Apr 5. doi: 10.1136/openhrt-2017-000668corr1; PMCID: PMC5888441; PMID: 29634047)
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888441/)
For more on nutritional deficiencies of magnesium caused by medications, see Uwe Gröber's Magnesium and Drugs, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539869/#!po=62.5000 with an excellent image of ways that drugs interfere with nutrient levels in the body, and a table specific to Magnesium. It lists conditions which may be missed by doctors as relating to magnesium deficiency, including arterial calcification, hypertension, insulin resistance, atherosclerosis, heart failure, and thrombosis, and describes disorders of magnesium metabolism as a principal, under-recognized, "driver" of cardiovascular disease.
That under-recognized was highlighted for me recently when a neighbor was told that calcium in his heart was okay, and given no treatment plan. This person has diabetes and hypertension. It makes even self-treatment potentially dangerous without having these conditions monitored for improvement which might make his medication levels too high.
As well, his own self treatment caused him to be greatly exhausted, possibly because the body was energetically moving the magnesium into place, and in the process not leaving energy for the personality, or alternatively could have been depleting other nutrients in the process of placing the magnesium. In either case, the opinion of the medical community had previously leaned toward psychological issues as if they were not also at the same time neurotransmitter issues. Since he was known to have depression (which can be caused by magnesium deficiency, see links at bottom), the condition was more likely to be treated as psychological, as if people with psychological conditions did not have more medical comorbidities than their healthy counterparts, not less.
So, a multifaceted problem. If he takes the magnesium, and it has a good effect, it's the placebo effect. If he takes the magnesium, and it exhausts him in the short-term, it's a psychological problem. In neither case is it treated as the medical problem that it truly is, unless the doctor is aware of recent studies showing the problems with lab testing.
How much it will treat the depression or the diabetes is questionable, since they probably have other causes as well, including, in the case of depression, the sheer fact of having the true cause of his medical conditions ignored and belittled. But the calcium in his heart and the blood pressure should receive more major improvements, and in the latter case, more dangerous ones without the medical recognition that will grant him medical monitoring.
Thus it is important to differentiate between the antioxidant improvements of the placebo effect, and an actual improvement, and of course, when they are happening at the same time, estimating how much improvement is real and how much is temporary, so as to avoid continuing or increasing a treatment beyond when it is useful, nor reducing one too much or too quickly due to temporary antioxidant-based improvements.7
It is likewise important, for the trust and self-esteem of the patient, to avoid decreasing their antioxidant levels by attributing to placebo effect something that is real. Because the negative or anti-placebo effect of dismissal of a patient's very real experience, whether correctly interpreted by the patient or not, does damage through reduced antioxidant levels, and the mandate of a doctor is: First, do no harm.
---------
Magnesium and clotting, regarding post-stroke depression:
Effect of magnesium on fibrin formation from lower molecular weight (LMW) fibrinogen
https://pubmed.ncbi.nlm.nih.gov/11153893/
Lipinski B, Lipinska I. Effect of magnesium on fibrin formation from lower molecular weight (LMW) fibrinogen. Magnes Res. 2000;13(4):233-237.
---
References regarding magnesium and depression:
From: Aging and Disease
JKL International LLC
Association between Serum Magnesium Levels and Depression in Stroke Patients
Aging Dis. 2016 Dec; 7(6): 687–690.
Published online 2016 Dec 1. doi: 10.14336/AD.2016.0402
PMCID: PMC5198859
PMID: 28053818
Yingying Gu, Kai Zhao, Xiaoqian Luan, Zhihua Liu, Yan Cai, Qiongzhang Wang, Beilei Zhu,* and Jincai He*
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198859/
---
Magnesium and major depression
Eby GA, Eby KL, Murk H.
https://www.ncbi.nlm.nih.gov/books/NBK507265/#_NBK507265_pubdet_
---
Role of magnesium supplementation in the treatment of depression: A randomized clinical trial
PLoS One. 2017; 12(6): e0180067.
Published online 2017 Jun 27. doi: 10.1371/journal.pone.0180067
PMCID: PMC5487054
PMID: 28654669
Emily K. Tarleton,#1,* Benjamin Littenberg,#1,2 Charles D. MacLean,1,2,‡ Amanda G. Kennedy,1,2,‡ and Christopher Daley3,‡
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487054/
---
Case Reports
Rapid recovery from major depression using magnesium treatment
George A Eby et al. Med Hypotheses. 2006.
Eby GA, Eby KL. Rapid recovery from major depression using magnesium treatment. Med Hypotheses. 2006;67(2):362-370. doi:10.1016/j.mehy.2006.01.047
https://pubmed.ncbi.nlm.nih.gov/16542786/
---
Magnesium for treatment-resistant depression: a review and hypothesis.
Eby GA 3rd, et al. Med Hypotheses. 2010. PMID: 19944540 Review.
Eby GA 3rd, Eby KL. Magnesium for treatment-resistant depression: a review and hypothesis. Med Hypotheses. 2010;74(4):649-660. doi:10.1016/j.mehy.2009.10.051
---
Effects of Magnesium Supplementation on Unipolar Depression: A Placebo-Controlled Study and Review of the Importance of Dosing and Magnesium Status in the Therapeutic Response
Beata Ryszewska-Pokraśniewicz, Anna Mach, [...], and Maria Radziwoń-Zaleska
Nutrients. 2018 Aug; 10(8): 1014.
Published online 2018 Aug 3. doi: 10.3390/nu10081014
PMCID: PMC6115747
PMID: 30081500
Beata Ryszewska-Pokraśniewicz,1 Anna Mach,2,* Michał Skalski,2 Piotr Januszko,2 Zbigniew M. Wawrzyniak,3 Ewa Poleszak,4 Gabriel Nowak,5,† Andrzej Pilc,5 and Maria Radziwoń-Zaleska2,†
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115747/
---
Review
Magnesium in depression
Anna Serefko et al. Pharmacol Rep. 2013.
Pharmacol Rep. 2013;65(3):547-54.
doi: 10.1016/s1734-1140(13)71032-6.
Authors
Anna Serefko 1, Aleksandra Szopa, Piotr Wlaź, Gabriel Nowak, Maria Radziwoń-Zaleska, Michał Skalski, Ewa Poleszak
PMID: 23950577
DOI: 10.1016/s1734-1140(13)71032-6
Serefko A, Szopa A, Wlaź P, et al. Magnesium in depression. Pharmacol Rep. 2013;65(3):547-554. doi:10.1016/s1734-1140(13)71032-6
https://pubmed.ncbi.nlm.nih.gov/23950577/
---
Magnesium and depression
Anna Serefko et al. Magnes Res. 2016.
Serefko A, Szopa A, Poleszak E. Magnesium and depression. Magnes Res. 2016;29(3):112-119. doi:10.1684/mrh.2016.0407
https://pubmed.ncbi.nlm.nih.gov/27910808/
---
©Deborah Barges July 2020 open access
