While 80% of psychiatrists would put a depressed person on an SSRI, only 40% of them would put themselves on an SSRI if they were depressed.

Even psychiatrists do not understand how SSRIs work: they think they are mood-boosting drugs that offer some kind of normalization or reset to the neurotransmitter effect of serotonin, but in fact they act through the whole body, have enormous impacts on mitochondrial function, interfere with the necessary benefits of intracellular serotonin and mitochondrial melatonin to mitochondrial energy production, and themselves enter cells where they can have disparate but sometimes powerful impacts on the sigma-1 receptor (beneficial but meant to be activated cyclically, not chronically) and themselves can act as mitochondrial poisons once they reach the mitochondria.

To make matters far worse, many people are prescribed SSRIs by general practitioners, who lack both an understanding of how SSRIs work and the expertise to do a thorough psychological evaluation of the person.

It may surprise you that SSRIs do not have a randomized controlled trial basis to justify the way they are used clinically, nor do they even have superior randomized controlled trial results to drug-free approaches!

For example, there are 52 trials in adults with SSRIs with the average lasting eight weeks, most lasting no longer than twelve weeks, and the longest lasting a year, and zero evidence justifying the average clinical use lasting five years.

While SSRIs have 52 trials and about 10,000 total subjects studied, supplements have 192 trials with just under 17,000 total subjects studied.

Psychotherapeutic approaches had 198 trials in adults with over 15,000 total subjects studied over a decade ago and have far more now.

Exercise approaches in adults have over 218 trials with just over 14,000 subjects studied.

So, just three classes of drug-free approaches to depression combined have twelve times as many clinical trials in adults as SSRIs have with almost five times as many total people studied.

What may surprise you even more — often a single supplement outperforms an SSRI when it is almost certain that a depressed person actually needs multiple corrections to their nutritional status.

This is often true in the average person without doing any testing, when individualizing correction of nutritional status would certainly provide superior results.

Nevertheless, these trials are not all of equal quality, and interpreting them is best done with biochemical and physiological expertise in how the treatments work to assemble how they can best be synergistically combined in different people.

Further, even some herbal medicines have impacts very similar to SSRIs and carry some of the same risks. Thus, understanding how the herbal medicines work and comparing their trials to the SSRI trials is necessary for safe implementation of a protocol.

To help you do this for yourself, or, if you are a health care practitioner, for your patients, I have analyzed the research and produced a 17-page how-to guide, How to Heal From Depression Without SSRIs or Other Drugs.

This synthesizes the best of a scientific and mechanistic understanding of how depression is caused and how to heal from it with an evidence-based analysis of the hundreds of randomized controlled trials showing human outcomes of improvement in depression.

This is not a review of the evidence. I will review the evidence in a separate article. This is strictly a step-by-step how-to guide.

It provides three approaches: a five-page guide to “throwing the kitchen sink” at it for people who need fast results; a three-page guide to “try it and see if it works” for people who want to engage the middle of the road approach between quick results and quality results; and a nine-page guide to “optimize it” for the people who want to invest time and money in a slow-and-steady-wins-the-race approach to secure the highest quality results for the long-term.

The Science Behind This Protocol

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While producing self-rated health scores from the things you care most about is the best way to not get led astray by proxy markers, tracking glucose, ketones, and lactate can add some more objective math to your tracking and can often act as a leading indicator of a problem to come or can help you interpret the nature of a problem you are currently experiencing.

Energy Metabolism Governs Everything, and these are the three markers of energy metabolism you can measure at home to reflect the state of your mitochondrial energy production.

The primary reason to track all three is that

• Glucose shows how efficiently your cells use carbs for energy.

• Ketones show you how your body chooses to use fat or carbs for energy.

• and lactate reveals whether your mitochondria are overstressed by the demands you are placing on them.

This protocol serves as a general framework for testing and interpreting these three markers. It provides you with details of how to get set up, best practices for testing, how to pick timepoints to test, normal ranges for all three markers, expected responses to eating meals, and then walks you through eight different patterns of change, giving you actionable solutions to each pattern you observe.

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Optimize Your Mitochondria At Home With Glucose, Ketones, And Lactate V2

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Optimize Your Mitochondria At Home With Glucose, Ketones, and Lactate

By Chris Masterjohn, PhD, 2025.

This protocol provides a general framework for interpreting glucose, ketones, and lactate when used for your own self-experiments, when using my overarching Optimization Framework, or when using any of my Protocols.

For the rationale behind testing glucose, ketones, and lactate, read the “Glucose, Ketones, and Lactate” section of Three Tests to Transform Your Health.

How to Get Setup and Start Testing

Obtain ​KetoMojo meter and strips​, Novabiomedical Lactate Plus ​meter​, Novabiomedical Lactate Plus ​strips​, and ​alcohol pads​. If you plan to do a LOT of testing, get ​extra KetoMojo strips​, extra ​lactate strips​, and ​extra 30g lancets.

When testing, wash your finger with soap, rinse well, then wipe with an alcohol pad, let air dry or lightly blot with a very clean tissue, then puncture your finger. Lightly massage your finger with soft lateral motion if needed but do not squeeze it. Wipe away the first 2-3 drops of blood with a very clean tissue, then test.

The meters can be finicky at first, especially the lactate meter. Put the edge of the strip at the surface of the drop and let it sip it up rather than shoving the strip into the drop. Make sure your drop of blood is big enough that the blood moves rapidly through the strip without stalling.

If you have trouble getting enough blood for this, try looking for the least calloused part of your finger. For many people, this is off to the side rather than the tip or the front face. If you cannot get enough blood to generate several large drops to wipe away prior to testing, you can try using a 28g lancet or a 21g lancet. The smaller the gauge the larger the needle, so you are sacrificing comfort and possibly risking more pain in order to get more blood. Ultimately, being able to wipe away two to three sizable drops before testing is necessary for accuracy.

When to Test

The most important time of day to test is soon after you wake up, while you are fasting, while you are still in the resting state and before you have gotten the chance to get riled up or do any meaningful activity.

Optionally, you can pick a second time to test if you find a meaningful reason to.

One reason to do so would be that you have a predictable daily cyclicality to a health problem you are trying to solve. For example, you always experience sleepiness a half hour after lunch or you always experience anxiety around sunset, or you always wake up at 3AM without being able to go back to sleep. If anything like this is true, measure at the point the problem is most activated, or at the time of day you expect the problem to be most activated.

Another reason to do so would be that your values are most abnormal at a certain time of day. The only way to know this is to test many time points during the day to sample what could be abnormal. Then, if you see a consistent pattern of abnormality at a repeating timepoint, use that as your second time point to test.

If you do an exploratory period of multiple tests throughout the day, reasonable time points to test apart from waking fasting would be just before each meal, one and two hours after each meal, and just before bed.

The best postprandial timepoint to use is one hour after you finish a meal. This is the most common time point reported in the literature postprandially, so it is easier to define what is “normal” compared to other time points.

You shouldn’t test during and after exercise unless you use external guidance about how to interpret exercise zones and lactate clearance in response to training regimens. To judge your general health, focus on the simpler interpretations of resting data here.

If you do a lot of testing, you will be doing repeated microdamage to your fingers. Try to rotate them as much as possible. If you can use each finger on a rotating basis, you can test daily but each finger will have ten days to recover between punctures.

Dealing With Variability

Since your finger prick will elicit a mix of capillary and venous blood alongside extracellular fluid and the contents of damaged cells, and since even the pure blood would be whole blood rather than plasma, you are going to get differences from a draw of venous plasma in the lab, and you are going to get more variability. You can limit this variability by following the guidelines above to remove two to three sizeable drops of blood before testing. You could also experiment with pricking your ear lobe instead of your finger.

However, if you are testing daily for weeks on each protocol regimen, as strongly advised in the Optimization Framework, the variability will average out over time, and by focusing on the averages you can avoid getting lost in the weeds.

One thing you should not do is second-guess abnormal data and retest it because you don’t trust it. Do any kind of validation experiments you want to assess the variability, but do them separately from your actual data collection. In order to minimize bias, you have to accept the data you generate without second-guessing and selectively repeating it.

How to Organize Your Data

Click here to download the Ultimate Optimization Spreadsheet.

Do not open it in Excel or any other desktop program. Immediately drag and drop it into Google Drive and double click to open it as a Google Sheet.

Otherwise, features will be lost.

If you are only testing waking, resting, fasted numbers, use the columns that are prelabeled as glucose, ketones, and lactate.

If you are measuring a second or third timepoint in the day, make a separate column for it. You can either rename the extracted variables and one of the self-rated variables as “afternoon glucose” and so on, or you can add additional variables as outlined at 18:43 in this video.

You do not want to mix and match different time points in the same column, because doing so will make it extremely messy to document protocol averages and rolling averages.

Normal Ranges

Cited values are in mg/dL for glucose and mmol/L for ketones and lactate. Online calculators allow you to interconvert these for glucose, ketones, and lactate.

Waking glucose should be under 90 and close to 80 mg/dL, with lower values being fine as long as you do not feel hangry, anxious, faint, or lose any neuromuscular function, energy, or cognitive capacity. Below 70 mg/dL can be suspected of being a problem, but often if your ketones rise to feed your brain adequately you can easily tolerate values lower than this.

Waking lactate should be 0.5-0.9 mmol/L.

Postprandial glucose should be under 140 at any time point and ideally close to 100 after one hour.

Postprandial lactate should be under 1.5 and ideally 0.9-1.2.

Ketones should be 0-0.2 mmol/L around the clock unless you are on a ketogenic diet or using MCT oil or large amounts of coconut. If you are on a ketogenic diet, you are probably not going to push much higher than 1.5 mmol/L, but if your diet is shifted sufficiently in favor of fat at the expense of both protein and carbohydrate, especially if you are also hypocaloric or if you are including MCT oil, it is possible for ketones to be pushed to 3-5 mmol/L and this is not necessarily abnormal. Ketones above 0.2 mmol/L on a non-ketogenic diet should be suspected as abnormal and ketones above 5 mmol/L on a strongly ketogenic diet should be suspected as a potential acidosis risk.

In response to a meal, especially in response to a carbohydrate-inclusive meal, glucose should go up, lactate should go up, and ketones should go down.

Interpreting Changes in These Numbers

If you are using one of my Protocols, the primary interpretation of how these numbers change is that if they move closer to the optimal range, what you are doing is working, and if they move further away from the optimal range, what you are doing is not working, or you have gone beyond your tolerance for a certain step. Consistent with the Optimization Framework, you are primarily relying on protocol step averages after you see in the visual charts that the rolling time-based averages have stabilized.

However, there are some notable change patterns that can help you further interpret these numbers even if you are using them without an existing protocol for exploratory purposes:

If glucose goes up and lactate goes down, this likely represents an impairment in glycolysis. You may be taking a medication that blocks glycolysis, such as aspirin, or you may have a dietary or metabolic toxin that blocks glycolysis, such as oxalate, or you may be deficient in a nutrient needed for glycolysis, such as niacin (vitamin B3) or potassium.

To manage oxalate, use my Oxalate Protocol.

The best way to increase niacin is to add one to three tablespoons of Sari Nutritional Yeast to anything that could use a cheesy flavor or to replace part of your regular meat with an organ blend such as US Wellness 75% Ground Beef With Heart, Kidney, and Liver. You can also add Niagen. If you do, you may use 300 milligrams a day for three to four days as a loading dose but then should start at a maintenance dose of ⅛ or ¼ of a capsule per day and titrate up slowly over time until the markers optimize. Any form of niacin should always be spread out as evenly across meals as is practical, and if you experience any adverse effects from it at doses that are helping to optimize your markers you can try matching it with an equal amount of trimethylglycine (TMG).

The best way to increase potassium is to increase the amount of potassium-rich foods in your diet, which include the lean portions of animal foods with juices consumed, lean portions of milk, egg whites (consume with yolks), tubers, legumes, fruits, and vegetables. Replacing refined grains with whole grains can help, but replacing grains altogether with foods from the list above helps much more. Replacing fat with those foods will help as well. Track your diet in Cronometer and get your food potassium up to at least 4.7 grams (4,700 milligrams) per day. If you use a supplement, review with your doctor that neither your medical conditions nor medications interfere with potassium excretion (explained in more detail in the Cheat Sheet); make sure you evenly distribute the supplement across meals, preferably taking it after a meal, or spreading it across the beginning and end of the meal; you can use citrate or gluconate, but if you supplement with grams per day you should start taking both citrate and gluconate and possibly other forms such as bicarbonate to avoid overdoing any one organic acid.

If glucose goes down and lactate goes up, this likely represents an improvement in glycolysis. If the lactate stays within the optimal range, the rise in lactate can be tolerated. Ideally, it self-resolves over a few days or a week with the lactate coming back down to where it was. If the lactate gets pushed out of the normal range or gets worse over time, this indicates that your respiratory chain is not keeping up with the improvement in glycolysis.

If the pyruvate dehydrogenase enzyme is limiting, the most likely solution is to improve your thiamin status. The best way to improve your thiamin status is to add one to three tablespoons of Sari Nutritional Yeast to anything that could use a cheesy flavor. If you need more, you can start with one to three droppers full of liquid thiamin if you digestively tolerate the glycerin, and then, if you still need more, move on to between a half capsule, slowly titrated up to as many as five capsules per day of TTFD. While using thiamin, watch carefully for a further increase in lactate and pull back to the dose that does not raise your lactate. If you cannot find a dose of thiamin that reverses the rise in lactate, you are most likely dealing with a respiratory chain impairment to be dealt with as described next.

If your respiratory chain is limited, this could be any one of 297 different genetic problems with a role for almost any of the essential nutrients. If you cannot resolve the rise in lactate out of the normal range by using the methods contained within the protocol you are using, Track Your Diet in Cronometer and make sure you are meeting all of my custom Nutrient Targets. If that does not work, run the Comprehensive Nutritional Screening and interpret it with the Cheat Sheet. If that does not work, run Mitome. If you are not resource-limited, you can run all of these at once and retest them as often as needed to arrive at the final resolution of the rise in lactate.

If lactate goes up without a change in glucose, by contrast, this indicates that you are stressing your pyruvate dehydrogenase or your or your respiratory chain with whatever you are doing. If you don’t have a solid empirical benefit to your health arising from your strategy, simply reverse it. If you do have an empirical benefit, try moderating the dose to one that does not raise lactate. If you cannot do so, you should explore alternative strategies to give you the same benefit without the rise in lactate, or revert to the ways to optimize your pyruvate dehydrogenase or respiratory chain in the two paragraphs directly preceding this one.

If glucose goes up without a change in lactate or ketones, this might indicate a blended effect of impaired glycolysis and respiratory chain function and you should moderate your strategy or reverse course as just described.

If glucose goes up and ketones go down this suggests that your carbohydrate supply is increasing, either because you are eating or absorbing more net carbs or because something is favoring greater glycogen breakdown. You should see if this self-resolves over several weeks, in which case you simply had to adjust to the greater glucose supply. However, if it does not show stable and linear improvement you should treat it as a case of overwhelmed glycolysis and should try the oxalate, niacin, and potassium strategies listed above. Otherwise you should engage in moderation or reversal of your strategy.

Ketones being abnormally high with normal glucose and lactate could be due to impaired utilization of ketones, in which case you should focus on suppressing fatty acid oxidation and ketogenesis with carbs and protein.

Abnormally high ketones could also be due to poor pyruvate carboxylase activity or poor respiratory chain function. This would be especially likely if you can demonstrate that eating carbs increases your ketones instead of decreasing them. This is called paradoxical postprandial ketogenesis. If you don’t have a severe problem, you may only be able to observe this after provoking it with an 18-hour fast and showing that ketones go up at the 15-minute mark. This would need to be shown after several repetitions compared to several observations of a control period (15 additional minutes of fasting) conducted in randomized order.

Pyruvate carboxylase activity can be improved with biotin or manganese, or by reducing oxalate levels.

To manage oxalate, use my Oxalate Protocol.

Manganese can be supplemented in 3-8 milligrams per day, but no one should supplement with manganese without first running the screening for manganese overload contained within my Manganese Detox Protocol.

Biotin can best be obtained as follows. First, make the base of your diet rich in grass-fed animal products, a diversity of fermented foods, and a large volume of fresh produce. Then, add one egg yolk equivalent for every 25 grams of non-collagen protein in your diet. Each egg yolk equivalent can be any of the following: one raw or cooked egg yolk with the white thrown in the trash; one whole egg boiled for at least four minutes; 1.5 fried eggs; 3.5 poached eggs; 8 grams of natto; 9 grams of chicken liver; or 36 grams of beef liver. If you need a supplement to obtain more, you can obtain low doses from Solgar 300 microgram tablets or from Life Extension 600 micrograms, which is a capsule that can be easily emptied into smaller doses. Higher doses can be obtained from Jarrow 5 milligrams, which is a cost-effective option, or Pure Encapsulations 8 milligrams, which is a brand that seems anecdotally to have the least likelihood of adverse response to low-level contaminants. Biotin should be slowly titrated up from the lowest dose you can find that lowers ketones without raising glucose or lactate, stabilizing at each dose before moving on, and increasing the dose until you hit the point of diminishing returns and then slightly pulling back.

If none of this works, you should assume the problem is in the respiratory chain, in which case you should use Cronometer, the Comprehensive Nutritional Screening, and Mitome as described in the second paragraph of the previous page.

If glucose and ketones go up together without a rise in lactate, this suggests either that your fatty acid oxidation is displacing your glucose utilization or that oxalate is accumulating and inhibiting glycolysis and simultaneously inhibiting the citric acid cycle. To address excess fatty acid oxidation try lowering your consumption of fat or your intake of riboflavin, pantothenic acid, and CoQ10. To manage oxalate, use my Oxalate Protocol.

If glucose, ketones, and lactate all rise together, you may have a blended problem of two or more of any of the above, but almost certainly are overburdening your respiratory chain. This strongly suggests you should reverse course, unless you are getting an empirical benefit, in which case you should fix your respiratory chain using Cronometer, the Comprehensive Nutritional Screening, and Mitome as described in the second paragraph of the previous page.

If you are checking all the boxes in What Everyone Should Be Doing For Their Health, are not in the middle of an emergency, and not suffering from a debilitating disorder that makes it impossible to safely take responsibility for optimizing, then you should consider whether you are happy with your results. If not, and if simply trying more low-hanging fruit does not give you what you want, it is time to optimize.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

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The Ultimate Guide To Optimize Anything

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The Ultimate Guide to Optimize Anything

By Chris Masterjohn, PhD, 2025.

This applies to anything in life, but the focus is on implementing this strategy for health using any type of health-promoting strategy, whether it be foods, supplements, exercise, biohacks, herbal compounds, or pharmaceuticals.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

This should be used as a framework for implementing any of my Protocols, and should be implemented after reading “How to Optimize Anything” to obtain proper context and detail and with examples to improve understanding.

How to Know Whether You Should Optimize

Use this decision-tree chart to decide whether optimization is the right strategy for you:

Define What You Are Optimizing

Define exactly what you want to optimize. Don’t rely on a proxy marker.

Rate Yourself On A Score of 1-5

If what you are optimizing is not already in the form of a number, turn it into one by rating yourself on a scale of 1-5.

Pre-specify the exact definitions of 1, 2, 3, 4, and 5. Hold yourself to these exact definitions throughout your optimization cycle.

Make your definitions such that you expect your first month of rating, if your health would remain the same as it has been, you would expect to hit an average of 3, but you would see at least a few 2s and at least a few 4s, but would not expect to see any 1s or 5s unless your health got substantially better or worse.

It does not matter whether you make the scale 1= bad to 5= great or the reverse. Pick whatever makes the most sense to you for what you are rating.

When you rate yourself, if you are unsure whether you should use one number or the one next to it, split the difference. For example, if you are unsure of whether you are a 3 or a 4, you are a 3.5.

Spend as much time as you need to pre-specifying your definitions so that you never have to think much about it again. When you rate yourself, spend no more than one minute doing it. Making it as easy as possible makes it sustainable.

Take Your Measurements Every Day

Take your measurements every day. In general, you should ignore the individual daily measurements and focus on the averages.

Never Second-Guess Your Data

If you question the validity of a data collection instrument you are using, perform a separate validation study according to the guidance of the manufacturer or according to whatever problem you believe needs to be addressed.

By contrast, never second-guess your data during the course of routine collection and measure it a second time just because you didn’t like or trust the first number. This introduces bias.

Collect Your Background Data

Your entire regimen should be characterized in one or several accessible places in case you need to cross-reference or extract some of that background data.

Your diet and supplements should be tracked in Cronometer.

Your workout should be tracked in an app like Jefit or an adequate substitute.

You may have other data that is intermittent, such as annual or quarterly lab testing.

All of this constitutes “Background Data.”

You may want to extract one or two background data variables to your optimization sheet to help with interpretation. You should do this if you think it is an intermediary (mediating the causal pathway between your strategy and your target) or a confounder (independently impacting your target making it hard to judge the impact of your strategy) and if it is variable enough to have an effect and if the variability is not so repeatable that its impact easily averages out over a few weeks.

Decide On the Strategy You are Testing

This could be one of the steps in any of my Protocols Series, or it could be something from ancestral traditions, something someone recommended, something that you found a scientific study supporting, or something you came up with yourself based on biochemical reasoning or intuition.

Download the Ultimate Optimization Spreadsheet

Download the Ultimate Optimization Spreadsheet here:

The Ultimate Optimization Spreadsheet 2025

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Do not open it in Excel or any other desktop program. Immediately drag and drop it into Google Drive and double click to open it as a Google Sheet.

Otherwise, features will be lost.

Self-rated variables are what you rate yourself on using a scale of 1-5.

Extracted variables are things you extract from your Background Data.

Glucose, ketones, and lactate are the key markers of energy metabolism you can measure at home, and you should measure your energy metabolism when you are in an optimization cycle because Energy Metabolism Governs Everything.

The sheet by default has three self-rated and two extracted variables alongside these three markers but you can use the sheet to track any eight variables without having to make complicated edits and the functionality will be preserved.

Make the following edits:

• Change self-rated and extracted variable names to reflect the variables you are measuring.
  
  

• For self-rated variables, replace each one’s name both in its data column as well as in its definition cell in the upper right, then fill in your succinct and precise definitions for 1, 2, 3, 4, and 5 for each of them.
  
  

• Click on the top chart. Click … in the upper right corner, edit chart. Then click “include hidden/filtered data.” Keep the chart editor open and do this for the rest of the charts. It will now only require you to click once on the chart and then click once on “include hidden/filtered data” and keep doing this until you do it for the eighth and final chart.

Baseline Data

Enter “Baseline Data” into column A at the top. Collect baseline data for at least three days and ideally a week or more. The less familiar you are with how your variables of interest behave, the longer your baseline period should be.

Test One Thing At a Time

This does not mean test “one vitamin” at a time or test “one exercise” at a time. It means test one strategy at a time. It could be a multivitamin, a B Complex, an entire training approach, a program a new coach gave you, or a radical change to your food groups. Whatever it is, decide exactly what it means and test this and this alone until you can make a conclusion.

Slowly Titrate Your Dose To the Point of Maximum Benefit

Your dose range should be derived from my Protocols or from the existing knowledge base. If you are testing a vitamin or mineral with a well characterized requirement, use the dietary reference intakes (such as the RDA or AI) or my Custom Nutrient Targets as the lowest dose and make the rest of the range based on randomized controlled trials or associations between food-based nutrient intakes. If what you are testing is not of this nature, use randomized controlled trials, association studies, case series and case reports, and independent anecdotes.

Titrate up your dose in the same increment as your starting dose.

Assume that the “dose” of anything (exercise volume, frequency and duration of sauna, milligrams of a nutrient, grams of a macronutrient, etc) will have a curve associated with benefit and harm that looks like this:

You can divide up the main zones like this:

You want to be just shy of the point of diminishing returns:

To get there, titrate up slowly until you experience a smaller benefit than you had obtained from earlier dose increases, then pull back to the last dose that had given you a big benefit.

If you add a strategy or increase a dose and nothing happens after a week, you can start moving more quickly until you see an effect. If the first effect you see is positive, you are at the bottom of the primary benefit curve and should titrate up until you find diminishing returns. If the first effect you see is negative, you are at the edge of the loss of benefit or adverse effect range and you should cut the dose down until you find a dose that provides a benefit without an adverse effect. If you cannot find such a dose, discard the strategy.

How Long to Spend At Each Dose

Give at least a week to see if an effect emerges.

If you see an effect, stay at any given dose until your variables of interest stabilize.

You know you have stabilized when the moving averages are all clustering together in a straight line, and the short-term data is not breaking out of this cluster indicating a new emerging trend.

Once you stabilize, you can move on to the next dose increment or to the next strategy.

When to Randomize

If you initially think you see a benefit but over time it seems to wear off or act inconsistently, you may benefit from performing a randomized controlled trial on yourself.

If the effect you think may be there is definitely worth knowing about, characterize the time for which you would have to conduct the trial.

Assess your observational data for the possible existence of a lead-in effect, which is the time for the benefit to onset or reach a stable point, and the possible existence of a washout requirement, which is the persistence of the benefit from some period after you stop the strategy.

Your randomized periods will need to include the part you are measuring plus a buffer of lead-in and washout if you determine that lead-in and washout periods are necessary.

Plan to randomize at least six pairs of trials, so that you have twelve total trial periods.

The old approach is your control, and the new approach you are testing against it is your intervention.

Your primary endpoint is the thing you are optimizing.

Calculate the average and standard deviation of your control and intervention period from your observational data.

Use a sample size calculator to see how many pairs of trials you need to randomize. Whichever period had a greater standard deviation, enter its mean and standard deviation for group 1. Enter the other mean for group 2. Hit “generate.” The number per group in the result is the number of pairs you are going to randomize. If it seems impractically high, make a rule that you will analyze your data at the exact half-way point. If it is convincing you will stop. If you are unsure you will finish the trial.

Use a coin flip or a random number generator set to a minimum of 1 and a maximum of 2. Establish two orders you are testing: control then intervention, or intervention then control. Assign each order to heads or tails, or to 1 or 2. Make a rule that all orders have to be used more than once. Use the coin flip or the generator until one of the orders has already been used for half the slots, then fill in the remainder with the opposite order so that they all get used the same number of times.

Note in your sheet the occurrence of the trial and which day belongs to which order, but make a separate sheet or tab where you organize everything by the trial design.

Run stats with Graphpad t-test calculator set to “enter or paste up to 2000 rows.” If your pairs were subject to a variable in a way that makes each pair more closely related than the non-paired trial periods (such as being conducted across a menstrual cycle or a period of linearly increasing vitamin D status), you can use a paired test, but you have to enter your data in the exact paired form. For example, if you randomized pairs of ten-day periods, you have to enter the average for each 10-day period rather than the daily data, and each member of a pair has to be in the same slot in each column so the pairs are side by side. If pairing is not indicated, you can enter your daily data and do not need to worry about the organization so much.

It will give you a two-tailed p value. If you had a very specific hypothesis of the data going one way and not the other such that you would be willing to forego the knowledge that it had truly gone in the opposite direction, you can cut this p value in half to arrive at a one-tailed p value. The p value is the likelihood that you would observe a difference of this value or greater had no real effect been present. Conventionally, less than 0.05 is significant, but this is arbitrary. This gives you a sense of how confident you can be that your effect is real. You are only trying to prove it to yourself so you can be somewhat liberal with your interpretation of the data.

Forming Your Conclusion

You can also use the t-test calculator to test differences in your protocols.

Ultimately you want to look for whether the size of the effect is worth whatever cost is associated with obtaining it, and if you are convinced, incorporate the strategy into your long-term protocol and move on.

When You Are Done Optimizing

You are done optimizing when you get the results you want or you are out of strategies.

If you have the results you want, pick a new optimization target, or exit the optimization cycle until you feel the need to enter it again.

If you are out of strategies, take a “deload” period from optimizing, then focusing on learning until you have found new things to try.

Staying Optimized Over the Long-Term

When you have optimized something, continue to track it or at least check in with it from time to time to keep it optimized. If you think something that worked before is now causing a problem, or is not necessary, use this optimization strategy to slim down your regimen. Intersperse periods of reflection on what you want to stay optimized so your optimization stays high-return.

Do your hands and feet tingle when they shouldn’t? Oxalate crystals have been found in peripheral nerves, where they can contribute to peripheral neuropathy.

Do you have trouble remembering things or summoning the brain power you used to have? Oxalate crystals have been found in the brain, where they contribute to cognitive decline.

How about tinnitus, vertigo, or trouble swallowing? These are all observed in oxalate-mediated ethylene glycol toxicity.

Pain in the joints, genitals, or kidneys? Could definitely be oxalate.

If you notice any powdery, cloudy, crusty, or crystal-like secretions in body fluids or exuding from the skin or other body surfaces, this is very likely an oxalate problem. If you have kidney stones, chances are they are made of oxalate.

But you don’t need these striking signs to have an oxalate problem.

Oxalate toward the top of the normal range is a powerful mitochondrial toxin that decreases citric acid cycle activity by 48%.

Since mitochondrial health is the master key to longevity, and since mitochondrial energy production supports all aspects of health, oxalate is a pervasive destroyer of both healthspan and lifespan.

You don’t need to have any of the tell-tale signs to have an oxalate problem. Impairing mitochondrial function is so broad in its scope that it could contribute to nearly any otherwise unexplained health problem.

For one person its allergies. For another, its twitching. For another, it’s fatigue.

Whether you have health problems you can’t explain or simply want to optimize, you want to get your oxalate under control.

Unfortunately, the sources of oxalate are often the very things we need to leverage for longevity: for example, glycine extends lifespan, but can be a source of oxalate; vitamin C reduces nearly every chronic disease risk, but can be a source of oxalate; xylitol can reduce dental problems, which correlate strongly with chronic disease, but too much drives up oxalate.

Some of this can be managed by appropriate moderation. For example, 2000 milligrams of vitamin C raises oxalate in almost everyone, but 400 milligrams only raises oxalate in some people, and 100-200 milligrams rarely raises oxalate.

However, some of it is highly individualized based on genetics. For some individuals, collagen raises oxalate but glycine doesn’t; for other individuals, glycine raises oxalate but collagen doesn’t; for yet others, a little bit extra B6 can make all the other stuff moot.

My Oxalate Protocol leads you through the reasons for initial suspicion of an oxalate problem, laboratory confirmation, a baseline diet phase, running further lab work, fixing nutrient deficiencies, and using whole genome sequencing to guide you toward the source of oxalate for you. It concludes with a series of experiments to perform independent of genetic analysis so that you can use gene-specific and gene-independent strategies to put together your personal protocol.

This protocol is a 7-page quick guide for dealing with oxalate issues that isolates all the highly actionable points into one simple place and walks you through how to select and implement them.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

The Protocol Series

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Glycine helps detoxify foreign chemicals and cool down our immune system when it gets out of hand.

High-dose glycine is a powerful antipsychotic in schizophrenia, showing just how powerful it is as a brain-boosting and brain-optimizing nutrient.

If animal studies are to be believed, glycine is central to lengthening lifespan.

Yet, glycine has a dark side. It can generate oxalate, which forms crystals in the kidneys, joints, and brain. Oxalate poisons the mitochondria throughout our body, and messes with the metabolism of neurotoxic D-lactate in the brain. Too much glycine can overload the respiratory chain, making it harder to produce cellular energy. And if glycine cannot be broken down effectively to CO2, it can accumulate to levels that cause headaches, or, when high enough, serious neurological problems.

So, how do we leverage all these benefits without risking any of the downside?

My 7-page Glycine Protocol outlines three approaches to boosting glycine status: the simple approach, which provides dietary principles for a baseline diet and for two levers to use to boost glycine status; the data-lite approach, which covers how to use glucose and lactate measurements to optimize glycine status; and the comprehensive approach, which covers how to use labwork to determine the exact reason your glycine levels might be low and how to fix the underlying problem. The last section covers how to deal with glycine levels that are too high, or problems that occur whenever glycine levels go up. This includes a number of deficiencies that can be fixed and concludes with five different approaches to deplete glycine from the body if needed.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

The Protocol Series

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While most people are diagnosed between the ages of 15 and 30 with the peak in people between the ages of 20 and 29, young children can develop Crohn’s and many people are diagnosed between the ages of 50 and 80.

Thus, if you have a first-degree relative with Crohn’s you should certainly be looking after your own digestive health to avoid developing it in the future, no matter how old you are.

Crohn’s causes abdominal pain, diarrhea, weight loss, and fatigue.

Medical management of Crohn’s can involve surgery, but surgery intrinsically damages the microbiome, and not everyone’s microbiome recovers from it. The relapse rate after surgery is over 80%.

It can also involve medications such as immunomodulators, steroids, and biologics, most of which are monoclonal antibodies to TNF-alpha. These medications come with an increased risk of respiratory infection, psoriasis, neurological problems, and symptomatic immune responses, and the jury is still out on whether they increase the risk of cancer.

Once you go on a biologic, the relapse rate is extremely high if you even try cutting the dose let alone going off of it.

On the other hand, the power of nutritional healing is extreme.

This can be seen starting at birth: babies who are breast-fed for one year or more have an 80% lower chance of developing Crohn’s compared to those who are only breast-fed for three or six months.

Crohn’s is strongly associated with industrialized economies, hinting that processed foods and their additives may be almost necessary for Crohn’s to occur.

Exclusive liquid formulas are just as effective as the most powerful medications in inducing remission, but most people are three times more likely to discontinue these diets than they are to discontinue steroids because they hate them, and because they experience heartburn, flatulence, diarrhea and vomiting.

In fact, exclusive liquid formulas are made from trash ingredients and have been shown to hurt the microbiome in a manner that predisposes to relapse as soon as people start reintroducing solid foods.

Many diets, such as the Specific Carbohydrate Diet, the low-FODMAP Diet, the IBD-Anti-Inflammatory Diet, the Crohn’s Disease Exclusion Diet, the Gronigen Anti-Inflammatory Diet, low-carbohydrate diets, high- and low-meat diets, high- and low-fiber diets, and low-microparticle diets have been evaluated in some form or another for efficacy in Crohn’s disease.

But the literature is a mess. Interpreting it properly requires dozens of hours of work, an understanding of trial design and statistics, and mechanistic expertise in the causation of Crohn’s.

I therefore have synthesized the most efficacious of the tested diets and the tested supplements with mechanistic research on what is required to optimize the microbiome, metabolic contributors to Crohn’s, and mechanical tension in the intestines to produce a four-page protocol for inducing and retaining remission.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

The Protocol Series

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Tremors, twitches, heart palpitations or spasms?

Any psychiatric or neurological issue can be a sulfur problem.

If you care about your mitochondrial health and your longevity, you need to care about your sulfur metabolism.

There are different types of sulfur molecules that can accumulate to toxic levels, so the problems aren’t always the same.

For one person, it’s fatigue and nausea. For another, it’s diarrhea or poor digestion. For yet another, it’s strange purple spots on their skin.

For another, it’s negative reactions to supplements like thiamin, glutathione, or B6.

For everyone, optimizing sulfur metabolism is key to mitochondrial health, wellness, performance, and longevity.

Unfortunately, some things that help can just as easily hurt. For example, we need CoQ10 to clear sulfur properly, but some people experience insomnia or overstimulation when they take CoQ10, even when their data makes it clear they need it.

There is both an art and a science when dealing with sulfur issues. This protocol walks you through both aspects. Because sulfur metabolism is so complex, it guides you through “Assembling Your Personal Protocol” by selecting from all the possible components to suit the protocol to your needs.

Beyond generally wanting to optimize your health, here is a list of specific reasons you would want to drill deep with this protocol:

• any psychiatric or neurological problem, difficulty sleeping, muscle tension, or excessive startling

• any issues with allergies or histamine

• fatigue, nausea, vomiting,

• “hangriness” that is not verifiably due to low blood sugar and resolved by stabilizing blood sugar

• diarrhea, excessive gastrointestinal transit time

• heart palpitations, twitches and spasms, chronic pain, tremors

• high estrogen, low testosterone, any problems that appear as high estrogen or low testosterone but are not accompanied by the expected changes in those hormones

• petechiae, purpura, cancer, anything resembling hypoxia such as blue hands and feet upon standing

• any sulfur-related odors such as rotten eggs or matches

• any form of intolerance to any dietary or supplemental component that contains sulfur anywhere in its structure, like thiamin or lipoic acid

• or any intolerance to any of the following: fasting, fasting-mimicking diets, ketogenic diets, any kind of catabolic state, B6, calcium, riboflavin, or CoQ10.

This protocol is a 10-page quick guide to dealing with sulfur issues that isolates all the highly actionable points into one simple place and walks you through how to select and implement them.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

The Protocol Series

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This 7-page quick guide is what you need to not get sick, and what to do if you sense an illness is coming on.

The Ultimate Guide to Optimizing Anything

My 8-page quick guide that can be used to pair with any protocol below to guarantee you get the results you are looking for.

Optimize Your Mitochondria At Home With Glucose, Ketones, and Lactate

A comprehensive quick-guide to interpretation of these three critical home-measured markers of mitochondrial health.

The Depression Protocol

The ultimate how-to guide to obtain resilient mental health while boosting mitochondrial function instead of strangling it.

The Oxalate Protocol

Oxalate causes crystals in the kidney, breasts, and brain, and is a powerful mitochondrial toxin that almost certainly shortens your lifespan and destroys your healthspan. This protocol is a 7-page quick guide for dealing with oxalate issues that isolates all the highly actionable points into one simple place and walks you through how to select and implement them.

The Glycine Protocol

This 7-Page Quick Guide to optimizing glycine guides you step-by-step through all the reasons your glycine levels or glycine tolerance could need improvement.

The Crohn’s Protocol

This four-page quick guide is a complete strategy to induce and maintain remission from Crohn's disease using diet and supplements.

The Sulfur Protocol

A 10-page quick guide to the art and science of assembling your personal sulfur protocol. Sulfur issues can be at the root of psychiatric and neurological issues, gastrointestinal issues, discolorations of the skin, allergies, histamine issues, fatigue, mitochondrial dysfunction, and much more.

The MTHFR Protocol

A 7-page quick guide to optimizing and personalizing your methylation using foods and supplements.

This is for anyone with MTHFR C677T or A1298C.

The Iron Deficiency Protocol

A 4-page quick guide for how to manage iron deficiency, incorporating my latest research on iron.

You don’t need to be anemic to need more iron. You can just have low sex hormones, low cortisol, a disrupted skin barrier, poor immunity, fatigue, hair loss, restless leg syndrome, or a lack of motivation and drive.

The Iron Overload Protocol

A 5-page quick guide for how to manage iron overload, incorporating the new information on manganese overload.

Too much iron in the body causes fatigue, joint pain, depression and mood swings, hair loss, chest pain, dizziness, impaired sexual function, menstrual problems, and abdominal pain. It raises cholesterol, increases the risk of Alzheimer’s and Parkinson’s, and it causes general wear and tear on tissues that accelerates the aging process.

How to Detox Manganese

An 8-page quick guide to getting rid of excess manganese.

If your libido is shot, your sperm count tanked, your mood is increasingly erratic, you’re depressed, anxious, or irritable, your muscles are tense, or you just have a headache, you might have too much manganese.

If your liver is damaged, your IQ is dropping, or your grades in school are suffering, that could be manganese too.

If you let it go on too long, you could wind up with Parkinson-like problems, with slow movements, loss of proper balance and posture, dragging your feet on the ground when you walk, rigidity, tremor, loss of facial expression, and small, cramped handwriting.

The COVID Guide

The ultimate nutritional guide to all things COVID, including long-COVID.

Healing From COVID Vaccine Side Effects

The ultimate nutritional guide to adverse effects of COVID vaccines.

You don’t need to be anemic to need more iron.

You can just have low sex hormones, low cortisol, a disrupted skin barrier, poor immunity, fatigue, hair loss, restless leg syndrome, or a lack of motivation and drive.

Iron is so powerful in normalizing hormones, in fact, that together with vitamin A it has been shown to be just as effective as testosterone replacement therapy in inducing puberty in boys who otherwise failed to undergo it.

Just think about what optimizing iron could do for an adult trying to say healthy during aging!

This protocol covers foods, supplements, inflammation-related strategies, and two genes that are worth considering in a speculative way to help with interpretations.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

This protocol is for reserved for Masterpass members. You can learn more about the Masterpass here.

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If your liver is damaged, your IQ is dropping, or your grades in school are suffering, that could be manganese too.

If you let it go on too long, you could wind up with Parkinson-like problems, with slow movements, loss of proper balance and posture, dragging your feet on the ground when you walk, rigidity, tremor, loss of facial expression, and small, cramped handwriting.

This could be from industrial exposure, the water supply, or eating a diet that is way too heavy in plants.

In addition to the ability of iron overload genes to promote manganese overload, there are also more recently discovered genes that cause isolated manganese overload.

This protocol leverages new research I have never shared before about how to accelerate the removal of manganese from the body, and covers how to know if this applies to you through proper testing and observational work, and what to do about it..

It is a 8-page quick guide, with the practical stuff up front and scientific details saved for the last few pages.

This protocol is for reserved for Masterpass members. You can learn more about the Masterpass here.

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Too much iron in the body causes fatigue, joint pain, depression and mood swings, hair loss, chest pain, dizziness, impaired sexual function, menstrual problems, and abdominal pain. It raises cholesterol, increases the risk of Alzheimer’s and Parkinson’s, and it causes general wear and tear on tissues that accelerates the aging process.

People predisposed to carry too much iron are also predisposed to carry too much manganese. 

Manganese overload causes headaches, irritability, insomnia, depression, and eventually loss of balance, problems walking normally, and Parkinson signs such as rigidity and tremor.

None of these symptoms are specific to either problem. For example, a complex I disorder can cause Parkinson’s, copper deficiency can cause tremors, having a rough life can cause depression, B vitamin deficiencies can cause irritability, and so on. 

Further, many of these issues could require opposite actions to solve. For example, fatigue and dizziness could be caused by iron deficiency or iron overload. If you do a coin flip, you have a 50% chance of selecting a strategy that makes you worse.

This underscores the importance of testing. 

Most approaches to testing are inadequate. For example, many people use ferritin as a marker of iron status. On its own, ferritin is uninterpretable. Ferritin is equally impacted by iron status, inflammation, and oxidative stress. A classic textbook form of anemia, called anemia of chronic disease or anemia of inflammation involves high ferritin, functional iron deficiency, and clinical anemia. This is because inflammation has increased the storage of iron in ferritin and made it unavailable to make red blood cells. If you just use ferritin, you will conclude such a person needs to donate blood or restrict iron, and this would just make their anemia worse.

Further, nearly all genetic testing misses the long tail of people with uncommon or rare mutations. Hence, many people have bloodwork suggesting iron overload and the genetics say “nope, you don’t have it,” but the genetics were only run on the two most common variants. But there are actually 215 variants known to cause iron overload, meaning that 99% of the variants are ignored.

Finally, it is almost universally unrecognized throughout the entire medical system and the entire health and wellness space that iron overload genes predispose someone equally to manganese overload. This is HUGE. Everything you could do to lower your iron status, donate blood, eat less iron, chelate iron, all of it will make manganese overload worse if you do not give equal care to the manganese problem.

About 9% of people need to care about this, and this protocol helps you determine whether that is you, and if it is, what to do about it.

This protocol is for reserved for Masterpass members. You can learn more about the Masterpass here.

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