Mitochondria and Energetic Failures: A New Understanding of Antidepressant Withdrawal? An Interview With Chris Masterjohn

Welcome to the Mad in America podcast. My name is Brooke Siem, and I am the author of the award-winning memoir on antidepressant withdrawal, May Cause Side Effects.

Today I am so excited because I am with Chris Masterjohn, PhD. Chris is a nutritional scientist, a former professor, and the founder of Mitome. With a PhD in nutritional science and years of research in mitochondrial biology, Chris’s work focuses on translating peer-reviewed science into practical tools for human health.

At Mitome, Dr. Masterjohn pioneered the first analysis designed to measure mitochondrial respiratory chain function directly, identifying individual energy bottlenecks and guiding personalized science-backed protocols to optimize the system responsible for over 90% of cellular energy production. His mission is to bring mitochondrial testing out of the rare disease space and into everyday health.

All of this is going to connect to his work around antidepressants and SSRIs, which is why I am excited to have him here today.

The transcript below has been edited for length and clarity. Listen to the audio of the interview here.

 

Brooke Siem: Chris, thank you so much for being here.

Chris Masterjohn: Thank you for having me. Good to be here.

Siem: I started researching your work back in the summer and I’d been following you for a while because I was interested in work on understanding SSRIs. In my case, I was put on a combination of Effexor XR and Wellbutrin XL when I was 15 as a kid, and my father had suddenly died. I was tossed on these drugs, and then I was on those drugs along with four others for other side effects from the antidepressants for the next 15 years.

Then I was suddenly pulled off of them by a psychiatrist, which sent me into horrific antidepressant withdrawal. 10 years later, I’m very lucky to say that I have healed, but I have spent so much of the past decade researching antidepressant withdrawal, trying to figure out what happened to me, and generally just unpacking the nightmare that is the psychiatric system in this country and all over the world. That is why I was so interested when I started reading your work, because you are talking about angles of this that I have suspected for quite a while, but hadn’t really seen anybody talk about.

That goes into my first question, which is, why do you care about antidepressants and antidepressant withdrawal? What led you to start researching this space?

Masterjohn: What I’ve been doing since around 2023 is a biochemical optimization program for individual clients. That often led me to do some research on why they were experiencing something in particular. Two of the people in that program had catastrophic post-SSRI energetic failures. The first one, he gave me an update at two weeks, six weeks, eight and a half months, and just recently at about 11 months.

He had looked for years to try to find improvement in his situation and really didn’t get any until the protocol that he just got. But now this guy, he had lost 17 pounds of muscle, and he gained it all back this year. He had stopped traveling because every time he was traveling somewhere, he wound up in the ER because he was having electrolyte issues and things like that. Now he’s traveling all over the world and is totally excited about life. In both of these cases, they had effects of either going off SSRIs or switching SSRIs or both, along with some other drugs like Wellbutrin.

The general picture of the two of them was that there was something about going off SSRIs and switching SSRIs that produced completely new problems that weren’t there before that were absolutely not psychological in nature.

Now, I’m not saying there weren’t psychological aspects to it. In the second case, there were things like de-realization episodes and things like that that occurred. But the main problem was a massive energetic deficit. You could see this because he was in his 20s, and he had spent an entire month where he couldn’t get out of bed to go to the bathroom. He had a portable bedside toilet. That one month was inside of a larger year where he didn’t even have the energy to be able to stand up in the shower.

Then the other one, not so much fatigue, but things that are still energetic in nature. For example, having to pee all the time, having tachycardia, having cramps and muscle spasms, all of those are just very obvious signs of energetic deficits because your ability to control the distribution of water and electrolytes and your ability to control muscular contraction is all something you do with energy.

I think everyone intuitively understands that in order to be strong, you need energy. They understand that in order to run fast, you need energy. But people generally don’t immediately grasp until they start studying physiology that you need energy to relax your muscles, and you need energy to control whether your muscles are contracted or relaxed.

The fact that they had each had a version of catastrophic energetic deficit, and the fact that I was specifically working on how to optimize people’s energy production, not entirely, but primarily with micronutrients. Because I was doing that, I was running comprehensive biochemical data on them, looking at what was happening inside their mitochondria, looking at what was happening to their metabolism of vitamins, minerals, carbohydrates, fats, and protein in their body.

How are they converting food to energy? How are they using that energy? What were the specific bottlenecks in that? I had access to all these data. But in order to really make sense of the historical picture, I needed to do that deep dive into how SSRIs were functioning. I’ll say that the massive success over the first 11 months of case number one really convinced me that I was onto something. That is why it made so much sense to keep investing the research time into it.

What I found convinced me that we totally don’t understand what serotonin actually does in the body. Then also, I don’t even think the researchers who are trying to study SSRI discontinuation syndrome have the slightest clue what’s causing it.

And I think they’re all completely distracted by what is essentially an intellectually bankrupt model of how serotonin and SSRIs work, which is the idea that they’re primarily acting inside the brain to pull levers on your personality. Everyone who knows about medicine and psychiatry knows that serotonin does other things besides acting on personality. That’s why we have things like serotonin syndrome.

If you overdose on serotonin syndrome, you’re breathing too fast, your body temperature goes too high, and lots of things happen that are not personality. But the main view of the average general practitioner, the average psychiatrist, the average person who goes on SSRIs, and the average researcher in the field is primarily thinking that the reason that serotonin is involved in depression or that antidepressants work in OCD or anxiety or depression, and the reason that people have withdrawal when they go off them, and they think that all of that is primarily about pulling levers inside the brain that change your personality, and maybe there’s side effects because you pulled too much on one of these levers.

Yes, people do understand that the brainstem is also using serotonin to regulate sort of autonomic function. But even extending it to that is still really missing the major picture, which is that serotonin primarily acts outside the brain, and it’s doing the same thing outside the brain that it’s doing in the brain.

Neurotransmitters explain some of the personality. They don’t explain the totality of human cognitive experience or the totality of human perception, or the totality of human behavior, or the totality of anything.

Serotonin is doing an analogous role in an energy metabolism throughout the entire body, but is in fact mostly acting outside the brain and is in fact mostly acting outside of neurons, probably even in the brain. To not be conscious of that is, I think, why no one can figure out what’s going wrong in SSRI discontinuation and in post-SSRI sexual dysfunction.

The big reason for that is that when SSRIs came out in the ’80s, they plucked up one aspect of serotonin, one particular model for understanding it, and then they basically made the entire scientific research operation about serotonin primarily act in the service of marketing the SSRIs. Even though if you go back in history, before SSRIs came out, serotonin was discovered in the gut. Then it was named after the fact that it’s in the blood.

But then, once SSRIs came out, the complete understanding of serotonin just moved into it. It’s inside the brain, and it’s pulling on these levers, and some of them are pulling on autonomic function, and the big ones are pulling on personality. Until we exit that model and start to understand serotonin and SSRIs in a way more holistic way, no one’s going to get anywhere on this.

That’s why it was worth my spending several months publishing all that stuff. But it does fundamentally go back to the fact that I was trying to look at the power of nutrition to help people in general, including a couple of people who were suffering from those problems.

Siem: You really hit on exactly what my problem is and what I’ve been seeing in the world of withdrawal and withdrawal research. This is such a tricky conversation to have if you’ve spent a lot of time in this world, because there’s so much progress in a lot of ways that has been made in the past.

Giovanni Fava first put out a paper in 2015 that started to really talk about antidepressant withdrawal, right? That’s the first time I saw it in literature. Then I think it was 2020 or 2021, where we started to see the word hyperbolic tapering get involved. And what I’m seeing now is that the idea that hyperbolic tapering and slow tapering is the way because of SERT occupancy, right? Will you explain SERT occupancy to the audience?

Masterjohn: SERT is the serotonin transporter, which is being blocked by the SSRIs. That type of tapering is not exclusive to SSRIs. It’s based on the general principle that if you’re taking a lot of a drug, the marginal increase in the dose that you’re taking is having less and less of an effect, because you’re basically maxing out what you can get out of that.

That’s just because the small doses are having a huge effect. When you go backwards, you get these really small effects from going down a large amount early. But then, as you go further down, you know, every five milligrams you cut, or every 10 milligrams you cut, or every two milligrams you cut is having way more physiological impact. Therefore, you need to go slower and slower and slower when you go down.

That is in the case of SSRIs, it’s driven by the fact that the specific SSRI is binding to the serotonin transporter more weakly as you go up in dose, but it’s just a very broadly generalizable dose-response effect.

Siem: In a lot of ways, it makes a lot of sense. I think it’s saved a lot of people a lot of suffering, rather than like with me, I was pulled off cold turkey, and I just have no idea what would have happened if I had been put on a more hyperbolic or slower taper. But the thing that I’ve started to see and the reason why I’m so interested in your work is that it’s not a panacea. Hyperbolic tapering does not help everybody. Very often, people can be going on a real great hyperbolic plan, and then they run into a wall at some seemingly arbitrary dose of an SSRI, and then they run into withdrawal, a full-body problem.

I started seeing that, because people would reach out to me, they’d be sharing their stories. There’s usually a collection of symptoms that come with it, right? They very often become hypersensitive. They can’t reinstate the dose without having problems. They can’t lower the dose without having problems. They are suddenly sensitive to caffeine or sugar, food, or supplements. They are kind of trapped in this damned if you do, damned if you don’t place.

When I started seeing that, it was telling me that the hyperbolic tapering strategy is part of the story, but it’s definitely not the whole story, at least not for all people.

Masterjohn: From a food-first, pharma-last approach, the very concept of using an SSRI is borderline insane because there are hundreds of randomized controlled trials on psychotherapy. There are hundreds of randomized controlled trials on nutrients. There are hundreds of randomized controlled trials on exercise. The evidence base does not put SSRIs in any special place, and so when people wind up on SSRIs, it’s almost never because there was a rationale of trying the least risky, highest potential payoff things first, that then led down the ladder to the SSRI. It’s usually because they were tried first, and so that’s just so foreign.

Siem: The reason why I brought that up is just that I think for folks who have been through it, we have a little bit of a different perspective. The reason why I say that is because so much of the time when people talk about it, it’s like, yeah, the psychological issues are there. Like, you know, the depression and anxiety, like that stuff, you can deal with that. You’ve been there. But it’s the insane intrusive thoughts and then the physical side effects that are typically what are really messing with people. When I think about the physical side effects, that’s what tells me, okay, this is more than just an emotional thing. There’s a full-body problem here.

When you started talking about mitochondria came into play, where I said, okay, I think this guy’s onto something. Can you basically explain your hypothesis about what SSRIs are doing to our cells in a way that even us English majors can understand?

Masterjohn: It would help for context to situate that in the context of what serotonin is doing. Serotonin, if you look at its history, was first discovered in the gut, and it was named enteramine. Enteramine means an amino acid. Amino acids are the building blocks of protein.

A few years later, another group finds that it’s in the blood. In fact, in the word serotonin, “sero” means serum. That’s what it means. It’s found in the blood. They said, what does it do in the blood? It constricts blood vessels. We now know that it doesn’t constrict blood vessels by acting on the neurological control of blood vessel constriction. It acts directly on serotonin receptors on the muscle cells and causes them to contract the blood vessels to make them smaller.

Siem: Which are found throughout the whole body, right?

Masterjohn: Throughout the entire body, yeah. If you didn’t have blood vessels in part of your body, it would die and it would fall off. The entire vasculature serves to go to your lungs, pick up oxygen, bring it to the heart, get pumped through the body, deliver the oxygen to tissues, carry the deoxygenated blood back, and repeat the cycle. All of that serotonin has the possibility of acting to constrict those blood vessels.

Think about the names of those two things. It’s drawing your attention to the fact that it’s in the gut and it’s in the blood. So, if you look at the word SSRI, the R is referring to “reuptake,” which is a brain-specific or nervous system-specific term. That’s referring to the fact that when two neurons talk to each other in order to carry out brain functions and nervous system functions, you’ve got one that releases serotonin, you’ve got the next one that’s going be responsive to it, and the point between them is the synapse. If you can block the reuptake of serotonin back into the first neuron, you can allow it to stay in the synapse longer, which means it activates the second neuron for longer.

How do we take the second S (“serotonin”) in SSRI and refer to something that’s in the blood, and then we take the R, and we pretend that it’s only in the brain? I think if you look at the history, like I said before, what essentially happened to that is that the explosion of interest in psychedelics in the ’60s and ’70s in the research community led to the dominance of the neurotransmitter model of the brain.

When psychedelics exploded, they showed that you could take microgram quantities of something and put it under your tongue, and you’re transported into a completely different state of consciousness for eight hours. This led to the idea of, wow, there are specific molecules that control specific receptors inside the brain, and we can just pull one lever and make you a completely different person. Then we can pull a different lever and make you a totally different person. This promised to be the fulfillment of the original idea of social control by allowing us to map out how all the different levers you could pull in the brain would impact psychology.

Serotonin is very specifically related to the psychedelics because all the psychedelics can act on serotonin receptors. D.L. Woolley, who is credited with discovering the role of serotonin as a neurotransmitter, his interest in serotonin was completely the idea that serotonin was an anti-metabolite of LSD.

If you just look at the history of SSRIs, he’s credited with being the foundation of SSRIs because he developed the understanding of serotonin as a neurotransmitter in the brain. Yes, serotonin’s in the brain, and yes, it does things, and yes, you can increase or decrease it, and you will get different results in behavior and personalities. Those things are true. But essentially, that was extracted. It’s the way that molecular biology was extracted from science in general to prioritize it above everything else.

My point is, you can make complete sense of why serotonin was named serotonin only by looking at that research, because now you’re looking at the role of serotonin in the blood and the lungs and so on. Okay, so enough of the history. You get the point.

Serotonin is all about making sure that under conditions of inadequate oxygen supply, your mitochondria, which are the powerhouse of the cell, are responsible for converting the food you eat into usable energy using oxygen in the air that you breathe to make the energy and distribute it in a way that is consistent with health. Serotonin is playing a role throughout the entire body, including in the brain, because you will always be undergoing times where the amount of oxygen compared to what the mitochondria need in that instant is inadequate. It’s jumping into that brink in order to bridge the gap and allow the mitochondria to function in that context and to adapt to it.

Now, some people, intuitively, when they hear me say not enough oxygen, they’re like, oh, when you’re drowning or, oh, if you’re getting strangled, but that’s not the right way to think about it. Every time you take a breath in, parts of your lungs are getting more oxygen than other parts. If you distribute blood to the lungs evenly, you’re going to waste a lot of the energy that the heart used to pump that blood to the lungs because it’s not going to get as much oxygen from some parts versus others.

This is more true for us, the way we breathe in the modern era, because most of us don’t breathe in a very healthy way. But it would always be true, no matter what, that you take a breath in, parts of your lungs are really oxygenated, and other parts are not so much. Serotonin plays the role of a traffic cop. In every single breath you take to make the blood go to where the oxygen is and not get wasted. Whenever you’re breathing, your heart is spending energy to pump blood to the lungs. The lungs are spending energy to inhale and exhale.

You need an ROI. You need a return on your investment. In order to do that efficiently, you need a traffic cop to make the blood go to where the oxygen is, so it doesn’t get wasted.

That’s one context. Another context is waking up in the morning. When you’re sleeping, one of the main benefits of deep sleep is that your mitochondria, which are working hard to make energy all day long, take a rest. They don’t go down to zero, but they become less active and produce less ATP. But you, the rest of your body, become so much less active that the demand for energy sinks below what the mitochondria are making, and you restore the energy that you used the previous day.

Now, if you look at depression, people with insomnia are two times more likely to experience depression. Why? Because brain energy is the primary determinant of your ability to resist depressive thoughts and thought patterns and to motivate the networks that are involved in optimism. If you don’t sleep, you don’t restore yesterday’s energy. Your brain lacks that energy, and it can’t go on.

When you wake up, your mitochondria, the demand goes way up. But you notice when you wake up, usually, you might have a great day, and there might be some people who wake up, and they’re ready to go. But most of us wake up, and there’s a little bit of lag before we feel good in the morning. That lag is that as soon as you wake up, your metabolic rate goes up. Then you stand up. Just standing up compared to sitting burns 30% more energy. I don’t know what standing up compared to lying down is, but it’s even more than that, right? And now you’re going to try to do something. You’re going to go into the kitchen and make coffee.

Now you’re walking, and so your demand is very rapidly going up. The mitochondria are going to take a half hour or an hour to really adjust to that. The key thing that allows that adaptation to go smoothly is that morning sunlight is the primary stimulus to make serotonin in your brain. That serotonin helps the oxygen get to the mitochondria and helps them adjust to the low oxygen state, and they catch up.

Siem: One of the more common complaints about people who are in pretty severe withdrawal is that mornings are worse and that they tend to get better as the day goes on. This is kind of explaining that a little bit, potentially.

Masterjohn: Yeah, I think that represents a dysfunction in the serotonin system. Then you might also have people who can’t tolerate morning sunlight, and that is a deeper mitochondrial dysfunction because the sunlight is activating the energy metabolism, but there’s something missing to allow it to take place.

There are not a lot of trials on morning sunlight, but the one randomized controlled trial that was done showed that it was twice as effective as exercise at inducing remission from depression. That’s because the primary driver of the content of serotonin in the brain is sunlight. You wake up in the morning, sunlight makes more serotonin, serotonin helps the mitochondria.

So let’s tie this back to the two original discoveries of serotonin. Suddenly, after we allow ourselves to think bigger than the neurotransmitter model of the brain, and that’s what serotonin is, suddenly, we can make tremendous sense out of the original discoveries. Why is 95% of the serotonin in your body in your gut? Because your gut is the most hypoxic part of your body.

Siem: Can you define hypoxic for the audience?

Masterjohn: Not having oxygen. The lining of the gut that does all the digestion does not have access to the oxygen that you’re breathing. The only way to get oxygen there is for the blood supply to come up underneath the gut lining and permeate the gut lining. You’ve got the blood supply coming up at the bottom. It’s got to go through a lot of cells before it gets up there. The oxygen level in the actual layer of the gut where the food is coming in is very, very low.

On top of that, it requires about 10% of your total energy budget to digest your food. Then on top of that, you’ve got your microbiome inside your gut that is consuming oxygen for its metabolism. The gut is very low level of oxygen. When you eat food, that food is going to take up 10% of your total of your total energy expenditure to digest. If that food sits in one segment of the gut, instead of moving, all of that oxygen utilization happens in that segment; that segment is essentially going to die, or it’s going to get very sick. If that doesn’t fix itself, it’s going to wind up dying because all of the oxygen is being spent, and it doesn’t have any access to anymore.

What does serotonin do? It stimulates gut motility to move the food along, and that helps each segment deal with the relative lack of oxygen. Why does serotonin constrict blood vessels? Because when it’s acting as a traffic cop in the lungs, it needs to constrict the blood vessels that would go to the parts of the lung that don’t have oxygen, and it allows the blood vessels to be open when it goes to the other parts. Every breath we take, serotonin is helping negotiate where, act as a traffic cop to make sure the blood goes to the well-oxygenated parts of our lungs.

If we still don’t have enough oxygen relative to our demands, serotonin is going to act in the brainstem to speed up the breathing rate. It’s going to act in the lungs to speed up the breathing rate and help us adapt to that. It’s going to then go into tissues and help their mitochondria deal with the lack of oxygen by improving mitochondrial function and improving mitochondrial resilience, and it’s doing this throughout the entire brain and throughout the body.

If you look, for example, at where serotonin receptors are, and the serotonin transmitters are, they’re important in every tissue, but the brain, the gut, and the reproductive tissues really stand out as being very high.

Siem: Which makes sense because when we talk about people who are in withdrawal or people who have pretty major side effects, honestly, the three that I hear the most are some sort of emotional blunting, which would be brain and emotions, theoretically, right? Gut issues, and then we have reproductive health issues like PSSD (post-SSRI sexual dysfunction).

Masterjohn: Yeah. You look everywhere from the lungs through the blood in the gut to the brain; everything about serotonin says that it’s about helping mitochondria deal with relative deficits of oxygen.

Now, SSRIs come into the picture, and the only real thing that’s acknowledged in psychiatry and medicine is that there are two weeks of nausea that occur at the beginning of SSRI treatment, and it’s because it’s acting on serotonin receptors in the gut. It’s overstimulating them, and it’s saying, by the way, if gut motility doesn’t work to support preventing parts of the gut from not having enough oxygen, what do you get? You either get diarrhea or you get vomiting. Those are the emergency valves for getting rid of food in the gut that the gut can’t handle digesting. Anyway, medicine acknowledges that there are a couple of weeks of nausea and potentially vomiting with early SSRI treatment, then it goes away. Why does it go away?

My theory is that you’re urinating out all the serotonin. There’s this idea out there that SSRIs boost your serotonin, and there’s another idea out there that some people who are most sophisticated think that they reset the serotonergic system or some kind of high-level fancy language like that. But SSRIs cause massive whole-body depletion of serotonin, and it’s completed by at least as early as the second week, and it’s mediated by causing you to pee out all the serotonin, and it lasts long-term. There’s no adaptation to it because if you look at people who have been on SSRIs for close to a year, they all have an average of 14-fold less serotonin in their blood.

Outside the brain, usually the general direction is the gut makes the serotonin, serotonin goes into the blood, the platelets take it up and store it, and the platelets release it under hypoxic stress, and some of that winds up making its way to the lungs or the liver to get degraded. Then the degradation products leave in the urine. That’s what normally happens, right? But when you take the SSRI, I think what’s happening is that the reason the nausea is usually self-limiting is that you don’t change the amount of serotonin in the gut at first, but you make it all extracellular, so it’s acting on the receptor to cause nausea and vomiting.

Now that more of it is extracellular, more of it goes into the blood, where it has access to the urine. Almost everything in the kidneys is just getting pushed into urine, no matter what it is, then the kidney uses its active metabolism to take what it wants back in, right? Something leaving the urine is usually passive. Something being conserved in the body is active. More serotonin winds up in the blood, more is exposed to the kidney, but the kidney now cannot use the serotonin transporter to suck it back up. All of that gets left in the urine.

Siem: It’s being blocked by the SSRI.

Masterjohn: Yes. Now, in the brain, most of the serotonin is being made in the brainstem, and so, it is the case that you are encouraging the serotonin to be more extracellular, and that might make it more likely that it enters the general circulation and can leave the body.

But it’s way less impacted because it’s being produced in the brain, and because the blood-brain barrier is not allowing constant back and forth of serotonin. It’s relatively compact. But it’s still the case that you would be shocked at how little there is in the research basis on what happens to brain serotonin when you’re on SSRIs.

There’s like four or five animal studies. It’s just bizarre that whatever anyone says about what happens to brain serotonin on SSRIs is not based on the evidence. It’s based on their theory. This is based on assumptions, and what I can say is that the evidence shows that there’s a handful of animal experiments that show totally conflicting results.

I believe I found the reason that they’re totally conflicting, and it’s because SSRIs, after they block the serotonin from entering the cell, go into the cell. The SSRI goes into the cell with 100% efficacy, such that the free amount of SSRI inside the cell is always going to be equal to the free amount of SSRI outside the cell, and they’re named by their actions on the outside of the cell, specifically in the brain, specifically between two neurons, as if they don’t do anything else.

But everywhere in the entire body, they’re going into the cells, and they’re doing other things. They’re activating other receptors that have nothing to do with the serotonin transport system that activate mitochondrial stress pathways, and part of those pathways is to increase serotonin production.

Siem: That’s the sigma-1 receptor?

Masterjohn: The sigma-1 receptor is the main receptor that is responsible for that effect. I had to piece together and parse experiments to make this fit together into a coherent story. But we know, for example, from one study, that the sigma-1 receptor increases the amount of serotonin that’s in the cell. We know from another experiment that it increases the amount of serotonin transporter in the membrane. We piece together what the things that it’s doing. We know that the different SSRIs bind to the sigma-1 receptor with a 52-fold difference in their activity.

The whole point of that discussion was that it looks like some SSRIs that activate the sigma-1 receptor increase brain serotonin and the ones that don’t decrease it. That’s what it looks like from the animal experiments.

Siem: In our last couple of minutes here, since we are going to do a part two, let me just break down what I’m hearing, and then you can tell me if it’s correct or not.

What I’ve really learned from your work is that our cells have a powerhouse called the mitochondria, which is where we produce energy to do everything from going to run up a mountain to going to work to sleeping to thinking to just breathing. We need our mitochondria working well to create energy for us to exist. Serotonin is vitally important to keeping the mitochondria healthy.

When we take an SSRI, we drastically interfere with how serotonin is naturally working in the cell and with the mitochondria all over the entire body. Then my extrapolation of that because I’m so interested in withdrawal specifically is that when we remove the SSRI, we have created so many issues within the way our cells are working that that is likely why there are so many different types of withdrawal and so many different bodily functions that go haywire and it’s not the same for person A as it is for person B.

Masterjohn: Yeah, I think that what’s happening is there are various effects on the mitochondria that differ between the different SSRIs, and then will interact with genetic and nutritional and other lifestyle, etc., variations in the human response to those things.

You mentioned at the top of the hour that I have a mitochondrial testing company. I ran that test on the two people in my program who had post-SSRI catastrophes, and they were on different SSRIs. They had different switching leading to their problems, but they had opposite effects on the abundance of mitochondria, right? You can wind up with too many mitochondria, or you can wind up with not enough, and some might say, well, why is too many harmful? It’s not so much because you have a lot of them. It’s because when you don’t have the normal break them down, build them up process, you can’t do quality control. If you wind up not able to break down your mitochondria, you wind up with too many dysfunctional mitochondria.

Then there are various specific things going on where it’s just they look like they have opposite, those two people had opposite responses to the whole oxygen regulation system that serotonin is involved with. I think that, and I currently am trying to organize research to look systematically at what happens when someone does a six-week, if we randomize people to a standard six-week taper or to a Horowitz-style lengthened, correctly structured taper, what’s happening to biochemistry and mitochondrial function during that.

But I think, yes, I think my hypothesis is that SSRI discontinuation is mitochondrial dysfunction. SSRIs have positive effects and negative effects on the mitochondria, but they also have effects that would be positive if they were stimulated naturally. The sigma-1 receptor, for example, is supposed to be cyclically and rhythmically activated through our stress response and our recovery. We’re supposed to go in and out of it like exercise.

If you take that and you pervert it into a pedal to the metal, like, I tied a brick to the gas pedal, and it’s on all the time, is that good or bad? Well, I think it’s a good thing gone bad because it’s not supposed to be activated that way.

Then I think the different people with their genetics, their nutrition, their lifestyle, and everything, their experience, everything that’s the last half a century or whatever went into who you are right now creates individual variations in what part of that system has gone wrong. On the other end of doing the research, we’re not going to find that there’s a one-size-fits-all solution for people. I think we’re going to find that there’s a variety, maybe there’s a few things that everyone should be doing, but there’s a lot of things that we need to actually elucidate that person’s biochemistry to understand what they should be doing.

Siem: Amazing. Thank you so much for your time here, Chris. Is there anything you would like to leave the audience with as we finish up Part 1 going into Part 2?

Masterjohn: Well, you can find me at chrismasterjohnphd.substack.com for my newsletter. You can find Mito.me for the mitochondrial testing. My message is always think about your mitochondria first and always use a food-first, pharma-last approach. It’s wonderful that we have the technology to be able to have pharmaceuticals, but we really need to resist the profit motive that is just massively overusing them and trying to use them first to solve problems that have much better, safer solutions when approached naturally.