TruthArchive.ai - Tweets Saved By @ChrisMasterjohn
@ChrisMasterjohn - Chris Masterjohn
I hate to break it to you, but your favorite "evidence-based pyramid" guru learned about evidence-based medicine from a meme. Yes, the pyramid is a meme. If it's what you know about evidence-based medicine, you are the Sesame Street character of evidence.
@ChrisMasterjohn - Chris Masterjohn
If you learned about evidence-based medicine from reading its founding documents, by contrast, you know it was essentially founded by Gordin Guyatt and David Sackett. https://t.co/RiuHod5JAH
@ChrisMasterjohn - Chris Masterjohn
You'd know they produced the first hierarchy of evidence in 1995. https://t.co/ZkgLUzpxRv
@ChrisMasterjohn - Chris Masterjohn
You know what else you'd know? That they had previously published a guide on conducting randomized controlled trials IN INDIVIDUAL PEOPLE. https://t.co/Dg180dldzZ
@ChrisMasterjohn - Chris Masterjohn
Why? Because "Large-scale randomized trials can provide only a partial guide and have not been or cannot be carried out for most clinical disorders."
@ChrisMasterjohn - Chris Masterjohn
As the article begins, "When deciding on optimal treatment for a patient, clinicians often cannot rely on the results of randomized controlled trials (RCTs). The relevant trial may never have been done, or the results of those that have been done may not apply to that patient.”
@ChrisMasterjohn - Chris Masterjohn
Why wouldn't they apply to the individual? Because the statistics used for RCTs apply to *groups.*
@ChrisMasterjohn - Chris Masterjohn
Stats ask the question of whether, if there were no effect in the population to which you are generalizing, you would have observed the effect apparent in the mean of your sample.
@ChrisMasterjohn - Chris Masterjohn
They are asking the question of whether you can confidentally generalize from the *average among people* in your trial to the *average among people* in the *population* you are making treatment recommendations to.
@ChrisMasterjohn - Chris Masterjohn
There is no trial in OTHER people that can tell you what will happen in YOU.
@ChrisMasterjohn - Chris Masterjohn
The founders of evidence-based medicine knew this, and they published on it.
@ChrisMasterjohn - Chris Masterjohn
If your favorite guru thinks that it is "evidence-based" to derive everything you do from the trial basis, they learned about evidence from a meme. Ignore them.
@ChrisMasterjohn - Chris Masterjohn
Other Hypoxia Studies in Rats
@ChrisMasterjohn - Chris Masterjohn
The authors of the mouse study discussed above had conducted another earlier study in rats showing that intermittent hypoxia is similar in the magnitude of its antidepressant effect to Prozac and imipramine...
@ChrisMasterjohn - Chris Masterjohn
...and that it lasts at least seven days after stopping the treatment, but did not compare its duration to that of the drugs.
@ChrisMasterjohn - Chris Masterjohn
A different group showed that in female rats but not male rats, altitude at 4500 feet or simulated altitude at 10,000 feet and 20,000 feet for one week caused a dose-dependent worsening on tests of depression and anxiety.
@ChrisMasterjohn - Chris Masterjohn
In another study this same group showed that female rats become anxious and anhedonic after altitude exposure.
@ChrisMasterjohn - Chris Masterjohn
The difference between these models is that the group showing benefits ran the tests a week after the hypoxia, whereas the group showing negative results seems to have run the tests immediately after removing the rats from their chambers.
@ChrisMasterjohn - Chris Masterjohn
If you view hypoxia stress similar to exercise, these findings are easy to reconcile. Right after exercising, your ability to complete the same task has gone down. Once you recover, your ability has gone up.
@ChrisMasterjohn - Chris Masterjohn
Intermittent Hypoxia Is an Essential Stimulus to Produce Positive Adaptations
@ChrisMasterjohn - Chris Masterjohn
The best way to synthesize all of this is that impaired oxidative energy production in the brain drives depression and anxiety, while SSRIs, tricyclic antidepressants, and ketamine are in variable ways helping to modify the response to this problem.
@ChrisMasterjohn - Chris Masterjohn
While the literature even on the antidepressant effect of ketamine is far more robust than the literature on the same effect of hypobaric hypoxia (where we only have rodent studies)...
@ChrisMasterjohn - Chris Masterjohn
...and while the literature on SSRIs is yet more vast, the rodent studies on hypobaric hypoxia indicate it could be a vastly superior way to produce a long-lasting antidepressant effect.
@ChrisMasterjohn - Chris Masterjohn
There are hundreds of reasons that anyone at sea level could have impaired brain energy metabolism, but in people who live at altitude, chronic hypoxia is excessive and plays a major role in depression and suicide.
@ChrisMasterjohn - Chris Masterjohn
The increased risk of depression and suicide at moderate altitude coexists with a lower all-cause mortality risk, which shows that this degree of altitude stress is causing a tradeoff, showing the dose has some benefits but is not optimal.
@ChrisMasterjohn - Chris Masterjohn
While chronic altitude stress raises the risk of depression and suicide, small doses of altitude stress can improve the brain’s ability to thrive under such stress, and thereby support psychological resilience.
@ChrisMasterjohn - Chris Masterjohn
In my review of the literature on simulated or real altitude raising testosterone in men, I concluded that 10-12 hours of 6500 feet using a simulated altitude tent three times a week is the best-performing protocol used in humans.
@ChrisMasterjohn - Chris Masterjohn
This makes me hope that this can be consolidated to 5-6 days per month spent hiking, skiing, snowboarding, or doing whatever you want at the top of a mountain about 6500 feet above sea level.
@ChrisMasterjohn - Chris Masterjohn
In male boxers and cyclists, stacking the hypoxia stress for five or six days starts to cause the acute loss of the initial testosterone benefit.
@ChrisMasterjohn - Chris Masterjohn
By contrast, spacing the protocol out three times a week allows the benefits to be maintained indefinitely, at least as far as has been studied.
@ChrisMasterjohn - Chris Masterjohn
However, I believe that 5-6 days in the mountains would slightly push you into “overreach” from which you would bounce back more hypoxia-fit, testosterone-loaded, and psychologically resilient...
@ChrisMasterjohn - Chris Masterjohn
...while the rest of the month at sea level would allow you to reset your capacity to handle another round.
@ChrisMasterjohn - Chris Masterjohn
In non-athletes and recovering drug addicts, testosterone increases linearly during a month spent hiking the mountains of Tibet.
@ChrisMasterjohn - Chris Masterjohn
While you could propose that natural mountain exposure is healthier than simulated altitude exposure, this cannot explain why depression and suicide is higher in people naturally living at altitude.
@ChrisMasterjohn - Chris Masterjohn
Therefore, I believe the answer is that high-level athletic activity is already adding enough into the physical stress bucket that they become very sensitive to exceeding the optimal dose...
@ChrisMasterjohn - Chris Masterjohn
...whereas people who are sedentary are chronically physically understressed and can take longer to accrue the initial benefits.
@ChrisMasterjohn - Chris Masterjohn
Nevertheless, athletic activity is the vocation of everyone who has a body, as Nike cofounder Bill Bowerman once pointed out, so I think we should take the studies in boxers and cyclists as a provisional target for the optimal dose of hypoxia stress.
@ChrisMasterjohn - Chris Masterjohn
This indicates that you want the equivalent of 15-20% of your time being spent at 6500 feet. We need more research to understand how changing the exact altitude changes the proportion of time that should be spent in it.
@ChrisMasterjohn - Chris Masterjohn
For example, maybe we could spend two or three days per month at 12,000 feet.
@ChrisMasterjohn - Chris Masterjohn
To replicate the protocol of the human studies, you can use an altitude tent during sleep and part of the evening for 10-12 hours three times a week and can probably substitute a simulated altitude mask.
@ChrisMasterjohn - Chris Masterjohn
If you live at altitude, you may already have an excessive hypoxia response. If you cannot change where you live, you can take the opposite approach. Start using an oxygen machine at a low, practical dose such as an hour a day, and titrate it up to where you start seeing improved mood and psychological resilience. Then, continue titrating it slowly by increasing the dose a little each week. When you reach the point of diminishing returns, stay there or pull back a little. Hypothetically you would want to achieve something equivalent to sea level for 80-85% of your total hours, but you may find that the minimal dose producing the maximal effect you are seeking is lower than that.
@ChrisMasterjohn - Chris Masterjohn
In the first article in this series, we saw that exercise is a more effective antidepressant than Prozac in mice, while Prozac is an exercise-enhancing drug that increases muscle mass and grip strength.
@ChrisMasterjohn - Chris Masterjohn
We then saw that a central role of serotonin is to mediate the hypoxia response.
@ChrisMasterjohn - Chris Masterjohn
We built on this to see that SSRIs modulate this role of serotonin in promoting mitochondrial tolerance of oxygen deprivation and even enter the cell to have their own impacts on mitochondrial function.
@ChrisMasterjohn - Chris Masterjohn
We now see that intermittent hypoxia has a much longer-lasting antidepressant impact than any pharmaceutical drugs.
@ChrisMasterjohn - Chris Masterjohn
All of this converges on seeing depression as fundamentally about mitochondrial energy production and the impact of these drugs being far more about intersecting with mitochondrial energy production than modulating psychological effects of specific neurotransmitters.
@ChrisMasterjohn - Chris Masterjohn
In the remainder of this series we will look at how to approach depression without pharmaceuticals, how to deal with SSRI-induced mitochondrial dysfunction, and how to deal with mitochondrial dysfunction induced by SSRI withdrawal.
@ChrisMasterjohn - Chris Masterjohn
For live links and scientific references, read this as an article on my web site: https://chrismasterjohnphd.substack.com/p/this-is-25x-more-effective-than-antidepressantsa
@ChrisMasterjohn - Chris Masterjohn
SSRIs Can Cause Severe Mitochondrial Dysfunction Installment eight in our series on understanding the truth about SSRIs. 🧵
@ChrisMasterjohn - Chris Masterjohn
In at least one out of 5,500 people – possibly at a much higher rate due to ignorance and underdiagnosis – sertraline (Zoloft) is such a potent mitochondrial poison that it can induce a devastating disease that has heretofore been thought to be a much rarer genetic disorder.
@ChrisMasterjohn - Chris Masterjohn
Adult-onset multiple acyl CoA dehydrogenase deficiency (MADD), also known as glutaric aciduria type II, is considered a rare genetic metabolic disorder with an incidence of one in 250,0000.
@ChrisMasterjohn - Chris Masterjohn
It is characterized by fat accumulation in skeletal muscle, exercise intolerance, and pain or weakness in the muscles.
@ChrisMasterjohn - Chris Masterjohn
Many cases may include other features, such as episodic vomiting, fatigue, difficult or rapid breathing, seizures, hypoglycemia, inflammation of the prostate, sensory neuropathy, and damage to the liver, heart, and skeletal muscle.
@ChrisMasterjohn - Chris Masterjohn
It turns out that sertraline (Zoloft) is 45 times more effective at inducing this otherwise genetic disorder than genetics themselves are.
@ChrisMasterjohn - Chris Masterjohn
In southeastern Sweden, there had been zero cases identified between 2004 and 2013.
@ChrisMasterjohn - Chris Masterjohn
Sertraline (Zoloft) was approved in Sweden in 2006 and in 2012 it became recommended as the first-line treatment for anxiety and depression. This increased the prescription rate by 48%. As of last year, 3.5% of people in Sweden were on sertraline.
@ChrisMasterjohn - Chris Masterjohn
Whereas zero cases of adult-onset MADD were diagnosed in southeastern Sweden between 2004 and 2013, nine cases were diagnosed between 2014 and 2024, but only two of them had a clear genetic basis.
@ChrisMasterjohn - Chris Masterjohn
In 2023, a North American group published a conference poster showing a woman who had a MADD-like biochemical profile on sertraline.
@ChrisMasterjohn - Chris Masterjohn
The profile completely normalized with two measurements taken off sertraline. Going back on sertraline made the biochemical profile diagnostic for MADD again.
@ChrisMasterjohn - Chris Masterjohn
This prompted the neurology unit of the Linköping University Department of Biomedical and Clinical Sciences in southeastern Sweden to retrospectively analyze these cases for an environmental cause.
@ChrisMasterjohn - Chris Masterjohn
All seven of the patients with no genetic explanation were on sertraline, and no other drug was taken by more than two people.
@ChrisMasterjohn - Chris Masterjohn
Whereas MADD is considered an extremely rare genetic disorder impacting one in 250,000, these cases imply that one in 5,500 sertraline users develops MADD. This is still rare, but it is no longer extremely rare. It implies that sertraline increases the risk of MADD 45-fold.
@ChrisMasterjohn - Chris Masterjohn
The publication of this paper rapidly led to similar retrospective analyses in western Sweden, North America, and Australia, bringing the total number of sertraline-induced MADD cases reported last year to thirty.
@ChrisMasterjohn - Chris Masterjohn
That this one inquiry led to the immediate discovery of 30 cases of sertraline-induced late-onset MADD in just four of the world’s 197 countries is quite remarkable given that the total number of genetic cases ever reported worldwide is close to 600.
@ChrisMasterjohn - Chris Masterjohn
It is even more shocking when you see that, as we cover below, genetic MADD is cured with food-achievable doses of riboflavin, while sertraline-induced MADD seems to require going off sertraline to fix...
@ChrisMasterjohn - Chris Masterjohn
...and some people even then do not even recover but are left permanently or quasi-permanently with weakness, pain, neuropathy, and difficulty breathing.
@ChrisMasterjohn - Chris Masterjohn
Three case reports of genetic MADD published between 2012 and 2022 mentioned the patient was on sertraline without any further comment. Most MADD case reports do not even catalog the medications the patient is on at the time of symptom onset.
@ChrisMasterjohn - Chris Masterjohn
In severe cases, MADD and other disorders causing fat accumulation in muscle can lead to rhabdomyolysis, often but not always in response to exercise. This is a state of muscle breakdown where muscle proteins spill into the urine and make it darkly colored.
@ChrisMasterjohn - Chris Masterjohn
Four case reports have been published on sertraline-induced rhabdomyolysis where it was not investigated whether it was driven by MADD. Given the other findings, these are likely severe cases of sertraline-induced MADD.
@ChrisMasterjohn - Chris Masterjohn
Given the general ignorance of this phenomenon and the fact that the question has not been asked in 193 out of 197 countries, these reports are surely just the tip of the iceberg.
@ChrisMasterjohn - Chris Masterjohn
This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.
@ChrisMasterjohn - Chris Masterjohn
Genetic Causes of MADD
@ChrisMasterjohn - Chris Masterjohn
MADD is considered a result of pathogenic mutations in the electron transferring flavoprotein dehydrogenase system, consisting of proteins encoded by the genes ETFA, ETFB, and ETFDH.
@ChrisMasterjohn - Chris Masterjohn
This system is responsible for delivering electrons to the mitochondrial respiratory chain from the oxidation of all fatty acids; the amino acids lysine and tryptophan; the branched-chain amino acids leucine, isoleucine, and valine; and from dimethylglycine and sarcosine, which can be derived from glycine, choline, or betaine (trimethylglycine or TMG).
@ChrisMasterjohn - Chris Masterjohn
The respiratory chain then uses these electrons to produce ATP, the primary energy currency of the cell. A backup in this system fundamentally impairs cellular energy production.
@ChrisMasterjohn - Chris Masterjohn
The system is dependent on riboflavin in the form of flavin adenine dinucleotide (FAD), so high-dose riboflavin supplementation is often helpful by improving the amount of FAD that can bind to, activate, stabilize the proteins involved and ensure their proper three-dimensional folding.
@ChrisMasterjohn - Chris Masterjohn
Due to the importance of riboflavin, mutations that hurt riboflavin metabolism (in FLAD1, SLC25A32, SLC52A1, SLC52A2, and SLC52A3 genes) can also cause MADD.
@ChrisMasterjohn - Chris Masterjohn
While not often acknowledged as a cause of MADD, impairments in the respiratory chain from the point downstream of the ETF dehydrogenase system, from CoQ10 through complexes III and IV, could cause similar metabolic impairments.
@ChrisMasterjohn - Chris Masterjohn
Riboflavin deficiency, while it also has broader effects, is sufficient to cause an acquired form of MADD.
@ChrisMasterjohn - Chris Masterjohn
SSRI Withdrawal Is Mitochondrial Dysfunction Installment seven in our series on understanding the truth about SSRIs. 🧵 https://t.co/IeABPwDvPK
@ChrisMasterjohn - Chris Masterjohn
My 51-page guide, "Methylene Blue: Biohacker's Delight, or Playing With Fire?" is now free: https://chrismasterjohnphd.substack.com/p/the-guide-to-methylene-blue
