Scientific expertise blended with out-of-the-box thinking for new practical ideas you can use to help yourself on your journey to vibrant health, by Chris Masterjohn, PhD.
Zoloft saved my life . . . at least for awhile. I've been suffering from suicidal depression and insomnia for years and had tried numerous medications not in the SSRI class. They either did nothing or made me worse. My doctor suggested trying Zoloft. I started on 50mg and felt better, but wanted to see what 100mg could do. The day after taking my first 100mg dose I slept nearly the entire day (and of course this is in the context of chronic insomnia). It was like taking a sleeping pill -- and SSRIs are not exactly sleeping pills. I felt much better too.
A little context would be helpful. I had taken 2 organic acid tests in about a 5 year span, the second of which was about a year before starting Zoloft. The first test indicated elevated (but still within "normal" range) 5-HIAA, the metabolite for serotonin. The second test a few years later indicated lab-high 5-HIAA. So whatever was happening, 1) involved serotonin and 2) was getting worse. I suppose this should have clued me in immediately to try a SSRI, but I wasn't exactly sure how to interpret the results. If my metabolites were high, maybe that meant I had too much serotonin? But, then again, maybe it meant I was dumping too much and therefore needed more? Turns out it was the latter. So that, plus a couple other factors, caused me to delay starting a SSRI a few years too long.
I would say the mood and sleep-enhancing effects lasted about 8 months (actually, the sedation effects wore off about half way through; the mood effects persisted). During that time, I tried going off Zoloft to see if I still needed it, and I quickly discovered that I did. The depression, rage and suicidal thoughts returned and a (variable) dose of Zoloft helped very much. After roughly 8 months or so the medication seemed to stop doing much, but I also felt better without it. I'm not out of the woods yet symptom-wise, but things are looking up.
So I just wanted to provide a counterexample to the "SSRIs are toxic" narrative here, because counterexamples are necessary data points. Sometimes SSRIs help and are needed.
You seem to have not read any of the preceding articles, and are writing to counter a "narrative" that you read in this article, which is an odd take given that the first installment began with "Prozac is a Performance-Enhancing Drug" which is hardly "SSRIs are toxic" and then most recently went into "SSRI Withdrawal is Mitochondrial Dysfunction" which went into the vastly more common problem that withdrawing from SSRIs causes mitochondrial dysfunction, again hard to reconcile to a simplistic "SSRIs are toxic" narrative.
Further, your just recounted having two tests which each have dozens of analytes and you narrowed in exclusively on 5-HIAA, which itself cannot distinguish between high or low serotonin since it could be increased both by a higher rate of production and a higher rate of catabolism, but wherein you in any case make the assumption that SSRIs are primarily about serotonin and then apply that to your condition, which itself should be dismissed based on the previous installment that "SSRIs are mitochondrial drugs."
Finally, while Zoloft may have helped you that does not mean you couldn't have gotten much better help from something much safer, it just means that you did not receive such help, but given the gross incompetence of the entire field of psychiatry and its complete and total capture by pharma, which has delayed our ability to understand any of this through four decades of completely perverting the science of serotonin, not having been helped otherwise doesn't tell us much about what we should be doing.
But, you are in any case correct, that some people find relief from SSRIs who did not obtain relief from earlier attempts at treatment.
My name is Brooke Siem, and I’m both a private performance chef working closely with Andy Galpin and Dan Garner, and one of the leading voices in the world of antidepressant withdrawal education and advocacy. I just came across your Substack began writing this note, because you’re articulating something I’ve intuited for years but never had the language to explain.
I was put on Effexor XR and Wellbutrin XL at age 15 in 2001, shortly after my father’s sudden death. At 30, I was pulled off Effexor cold turkey by a psychiatrist and plunged into a withdrawal so horrific that I ended up with a book deal. MAY CAUSE SIDE EFFECTS was published in 2022, and since then—with the help of media coverage and appearances in The Washington Post, The New York Post, Good Morning America, The Mikhaila Peterson Podcast, and The Art of Being Well with Dr. Will Cole—I’ve become something of a recognized expert on the topic. (Though I still find that title baffling, given I don’t have a PhD.)
Through my work in performance nutrition—customizing protocols for elite athletes based on insane amounts of biological data—I’ve come to believe that antidepressant withdrawal is driven by far more than SERT occupancy or plasma concentrations. But most of the thought leadership in the space is still stuck in receptor-centric models. Meanwhile, thousands of people are caught in limbo: they can’t tolerate their medications anymore, but can’t taper either.
In my one-on-one work with people in withdrawal, I’ve seen symptom improvement in the range of 40–60% on an animal-based diet—assuming no histamine issues, which are surprisingly common in withdrawal. That’s encouraging, but it’s only part of the puzzle.
Your work is the first I’ve seen that meaningfully addresses what might be happening under the hood—and I’d love to learn more. I imagine there could be a real opportunity for alignment between our approaches. If you’re open to a conversation, I’d be grateful for 20–30 minutes of your time to talk through what you’re seeing, and to explore ways I might support or contribute to your efforts.
Thank you so much Chris for the incredible work your doing on SSRIs and their long term effects. So many people dismissed my suffering when I went through withdrawal coming off that garbage. Your research has given me so much clarity on what was happening in my body and it gives me hope on how to fully recover. Thank you again for shining light on the dark side of psychotropics.
Have you considered submitting this series on SSRI's to websites like Mad In America? I would think their readers would find your info incredibly helpful. Also Theinnercompass.org
Damn I really should get my acylcarnitine profile checked out and stay the hell away from SSRIs. DXM(a cough medicine) is a sigma-1 agonist aswell. Would taking that lead to more intracellular melatonin production and maybe performance enhancement via mitochondrial biogenesis ?
I think chronic stimulation of sigma-1 is an incredibly horrible approach that only the totally disgraceful and incompetent pharma industry could come up with.
It's a receptor that is supposed to be cyclically stimulated by stress.
You could, I suppose, find a way to purposefully cycle a drug to achieve that, but you'd be much better off using non-drug approaches.
If the SSRI industry wasn't purposefully holding back our understanding for decades, and if the emerging psychedelic movement wasn't so hung up on tripping and instead studied why ketamine can induce improvement at doses that don't cause perceptual changes and shifted into understanding the impact of mitochondrial function of psychedelics, we would perhaps make faster progress in understanding what the endogenous agonists of the sigma-1 receptor even are.
Instead we are perpetuating a loop that was originally created in the 60s, where literally the population-wide uptake of LSD gave us the serotonin/brain science that led to the development of SSRIs and now we are giving up on SSRIs and going to mushrooms. lmao.
I will in any case be writing on something 30 times more effective than ketamine and we can start there.
Cyclic vomiting is clearly related to an inborn error of metabolism, but it could be a variety of them and anyone with it should have a full biochemical workup.
🙏 My son had complete metabolic testing. The metabolic geneticist said he didn't have metabolic defects but I ordered his medical records and many of his lab results were abnormal.
I'm not sure they even know what they are looking at on the tests - outside a few diagnosable diseases.
They have what can quantitatively be said to be on the whole no idea what they are doing.
This can be proven mathematically. Essentially this goes as follows.
Jerry Vockley has shown that full-blown diseases can result from two heterozygous mutations in a closely related pathway where both are within "normal" diagnostically but the combined result is just as full-blown disease as homozygous mutations that would lead to a diagnosis.
This has received very little attention in the field.
I wrote to Vockley and I asked him this.
Is it not mathematically impossible for these not to represent >99% of such cases?
If you take the probability that enzyme A has a pathogenic mutation in both the maternal and maternal allele, and then you compare it to the probability that two different enzymes in the same pathway have their own pathogenic mutations, the odds are at least an order of magnitude higher that synergistic heterozygosity will be present. If you then expand this to two enzymes in different pathways that interact on the course of catabolizing one macronutrient to ATP, for example a fatty acid oxidation with an ETF dehydrogenase enzyme or a complex III or 4 mutation or something in CoQ10 synthesis, you now get *astronomical* odds in favor of synergistic heterozygosity.
Vockley said yes, he thinks about the math the exact same way, but it is difficult to prove causation in the cases.
But if you are trying to solve a rare problem you cannot get hung up on proving causation, you need to use a flexible model that allows you to make the best judgment, act on it, and revise as necessary.
What this shows is that most "rare diseases" will NEVER be solved, because what we are observing is that the medical diagnostic model has reached its limit to solve them. All it can accomplish now is to make trivial marginal eeking out of a new diagnosis here and there. Most "rare diseases" aren't something entirely new. They are mixed and matched pieces of existing diseases, where each piece qualifies as "normal" and thereby precludes any diagnosis.
Medicine has to EXIT its diagnostic model to help most people with severe problems who are not currently helped.
😪 My son had CVS for years, ended up in the hospital when he had episodes.
They say most children with CVS (also known as abdominal migraines) stop getting them and develop actual migraines as adults. It's more common if a mother has migraines for her child to have abdominal migraines.
I felt it might be tied to his immune defects, since his thymus organ was taken from him as a newborn during heart surgery. After that, he had chronic immune defects. I have migraines and immune problems of my own, UTI's, chronic candida, chronic EBV. I've gotten some of the infections under control but the migraines remain.
Ps the thymus organ, thymus peptides affect mitochondria. Thymosin beta 4 (Tβ4) has been shown to play a role in mitochondrial function and dynamics, particularly in relation to cell survival and tissue regeneration. It can facilitate mitochondrial transfer between cells, impacting tissue repair and regeneration, and it also plays a role in regulating apoptosis and oxidative stress within mitochondria.
Tβ4 has been shown to enhance the transfer of mitochondria from adipose-derived stem cells (ADSCs) to other cells, like adipocytes and new blood vessels, within fat grafts via tunneling nanotubes. It's linked to the upregulation of the Rac/F-actin pathway, which is crucial for forming nanotubes.
Doctors who take thymus organs from newborn babies, like what was done to my son, have been causing irreparable harm for 5 decades now.
Acerola with bioflavanoids in massive doses has helped me. 35-70 grams a day. It also helps my leg cramps and vein issues but nothing completely takes it all away.
That’s a shame. So sorry. At least there are so many in the modern health space trying To address this if you can avoid quackery. I’ve heard migraines are easy to stop with salt water and aspirin, but I can’t remember might be disinfo.
When my child started eating around 9 months, he would vomit like crazy and would usually require IV intervention. Allergy tests came back ok, and he was diagnosed with FPIES. Many foods would trigger it like 1 cheerio, but some would not.
Chris excellent series.Not specifically a SSRI but curious on your opinion on another antidepressant,
Mirtazapine that’s been shown to help mitochondria in vivo.
A serotonergic 5- hydroxytryptamine 2/3 (5HT2/3)
receptor antagonist and
noradrenergic antidepressant, which has been used off-label for management of gastroparesis.[14] It blocks histamine H1 and serotonin 5-HTZA, 5-HT2C, and 5-HT receptors and stimulates 5-HT1A receptors
in both peripheral and the central nervous system.[15]
Stimulation of 5-HT1A receptors is
believed to be responsible for its antidepressant and anxiolytic effects,
whereas blockade of H1, 5-HT2A, and 5-HT2C receptors also contributes partly to some of its anxiolytic and sedative effects.
Mirtazapine's impact on central neural systems involved in mood regulation could have partly contributed to its orexic property.
I wonder what NDRI like Wellbutrin might lead to, what a person might take to avoid long term effects.
I looked up Acyl-CoA Dehydrogenase (ACAD) deficiencies. Taking L-carnitine and riboflavin (vitamin B2) are commonly supplemented. In some cases, Coenzyme Q10 and triheptanoin may also be used. Dietary modifications like restricting long-chain fats and increasing medium-chain triglycerides (MCT) are crucial.
But how can we fix this? How can someone heal or have better quality of life if they are effected?
See "the bottom line" section.
Anyone can stop taking these drugs full stop as they are useless addressing the cause of the symptoms they claim to fix.
No, see the last article, many people get demolished by stopping, higher rate with stopping cold turkey.
Typo near beginning 250,0000.
Zoloft saved my life . . . at least for awhile. I've been suffering from suicidal depression and insomnia for years and had tried numerous medications not in the SSRI class. They either did nothing or made me worse. My doctor suggested trying Zoloft. I started on 50mg and felt better, but wanted to see what 100mg could do. The day after taking my first 100mg dose I slept nearly the entire day (and of course this is in the context of chronic insomnia). It was like taking a sleeping pill -- and SSRIs are not exactly sleeping pills. I felt much better too.
A little context would be helpful. I had taken 2 organic acid tests in about a 5 year span, the second of which was about a year before starting Zoloft. The first test indicated elevated (but still within "normal" range) 5-HIAA, the metabolite for serotonin. The second test a few years later indicated lab-high 5-HIAA. So whatever was happening, 1) involved serotonin and 2) was getting worse. I suppose this should have clued me in immediately to try a SSRI, but I wasn't exactly sure how to interpret the results. If my metabolites were high, maybe that meant I had too much serotonin? But, then again, maybe it meant I was dumping too much and therefore needed more? Turns out it was the latter. So that, plus a couple other factors, caused me to delay starting a SSRI a few years too long.
I would say the mood and sleep-enhancing effects lasted about 8 months (actually, the sedation effects wore off about half way through; the mood effects persisted). During that time, I tried going off Zoloft to see if I still needed it, and I quickly discovered that I did. The depression, rage and suicidal thoughts returned and a (variable) dose of Zoloft helped very much. After roughly 8 months or so the medication seemed to stop doing much, but I also felt better without it. I'm not out of the woods yet symptom-wise, but things are looking up.
So I just wanted to provide a counterexample to the "SSRIs are toxic" narrative here, because counterexamples are necessary data points. Sometimes SSRIs help and are needed.
You seem to have not read any of the preceding articles, and are writing to counter a "narrative" that you read in this article, which is an odd take given that the first installment began with "Prozac is a Performance-Enhancing Drug" which is hardly "SSRIs are toxic" and then most recently went into "SSRI Withdrawal is Mitochondrial Dysfunction" which went into the vastly more common problem that withdrawing from SSRIs causes mitochondrial dysfunction, again hard to reconcile to a simplistic "SSRIs are toxic" narrative.
Further, your just recounted having two tests which each have dozens of analytes and you narrowed in exclusively on 5-HIAA, which itself cannot distinguish between high or low serotonin since it could be increased both by a higher rate of production and a higher rate of catabolism, but wherein you in any case make the assumption that SSRIs are primarily about serotonin and then apply that to your condition, which itself should be dismissed based on the previous installment that "SSRIs are mitochondrial drugs."
Finally, while Zoloft may have helped you that does not mean you couldn't have gotten much better help from something much safer, it just means that you did not receive such help, but given the gross incompetence of the entire field of psychiatry and its complete and total capture by pharma, which has delayed our ability to understand any of this through four decades of completely perverting the science of serotonin, not having been helped otherwise doesn't tell us much about what we should be doing.
But, you are in any case correct, that some people find relief from SSRIs who did not obtain relief from earlier attempts at treatment.
So taking b2 can help with MADD or overall mitochondria heath from ssris
Hi Chris,
My name is Brooke Siem, and I’m both a private performance chef working closely with Andy Galpin and Dan Garner, and one of the leading voices in the world of antidepressant withdrawal education and advocacy. I just came across your Substack began writing this note, because you’re articulating something I’ve intuited for years but never had the language to explain.
I was put on Effexor XR and Wellbutrin XL at age 15 in 2001, shortly after my father’s sudden death. At 30, I was pulled off Effexor cold turkey by a psychiatrist and plunged into a withdrawal so horrific that I ended up with a book deal. MAY CAUSE SIDE EFFECTS was published in 2022, and since then—with the help of media coverage and appearances in The Washington Post, The New York Post, Good Morning America, The Mikhaila Peterson Podcast, and The Art of Being Well with Dr. Will Cole—I’ve become something of a recognized expert on the topic. (Though I still find that title baffling, given I don’t have a PhD.)
Through my work in performance nutrition—customizing protocols for elite athletes based on insane amounts of biological data—I’ve come to believe that antidepressant withdrawal is driven by far more than SERT occupancy or plasma concentrations. But most of the thought leadership in the space is still stuck in receptor-centric models. Meanwhile, thousands of people are caught in limbo: they can’t tolerate their medications anymore, but can’t taper either.
In my one-on-one work with people in withdrawal, I’ve seen symptom improvement in the range of 40–60% on an animal-based diet—assuming no histamine issues, which are surprisingly common in withdrawal. That’s encouraging, but it’s only part of the puzzle.
Your work is the first I’ve seen that meaningfully addresses what might be happening under the hood—and I’d love to learn more. I imagine there could be a real opportunity for alignment between our approaches. If you’re open to a conversation, I’d be grateful for 20–30 minutes of your time to talk through what you’re seeing, and to explore ways I might support or contribute to your efforts.
-Brooke
Thank you so much Chris for the incredible work your doing on SSRIs and their long term effects. So many people dismissed my suffering when I went through withdrawal coming off that garbage. Your research has given me so much clarity on what was happening in my body and it gives me hope on how to fully recover. Thank you again for shining light on the dark side of psychotropics.
May I ask how you healed?
How are you getting better from this?
Have you considered submitting this series on SSRI's to websites like Mad In America? I would think their readers would find your info incredibly helpful. Also Theinnercompass.org
Damn I really should get my acylcarnitine profile checked out and stay the hell away from SSRIs. DXM(a cough medicine) is a sigma-1 agonist aswell. Would taking that lead to more intracellular melatonin production and maybe performance enhancement via mitochondrial biogenesis ?
I think chronic stimulation of sigma-1 is an incredibly horrible approach that only the totally disgraceful and incompetent pharma industry could come up with.
It's a receptor that is supposed to be cyclically stimulated by stress.
You could, I suppose, find a way to purposefully cycle a drug to achieve that, but you'd be much better off using non-drug approaches.
If the SSRI industry wasn't purposefully holding back our understanding for decades, and if the emerging psychedelic movement wasn't so hung up on tripping and instead studied why ketamine can induce improvement at doses that don't cause perceptual changes and shifted into understanding the impact of mitochondrial function of psychedelics, we would perhaps make faster progress in understanding what the endogenous agonists of the sigma-1 receptor even are.
Instead we are perpetuating a loop that was originally created in the 60s, where literally the population-wide uptake of LSD gave us the serotonin/brain science that led to the development of SSRIs and now we are giving up on SSRIs and going to mushrooms. lmao.
I will in any case be writing on something 30 times more effective than ketamine and we can start there.
Looking forward to this. Totally agree on pharma's culpability. Just appalling.
Is Amitriptyline a mitochondrial poison like other SSRIs? Dr Chris or others. Let me know.
Yes can be but I'm focusing on SSRIs for now.
Chris! Do you think Cyclic Vomiting Syndrome could be tied to MADD? If so would riboflavin supplementation be helpful? Thank you always❤️. Tracey
Cyclic vomiting is clearly related to an inborn error of metabolism, but it could be a variety of them and anyone with it should have a full biochemical workup.
🙏 My son had complete metabolic testing. The metabolic geneticist said he didn't have metabolic defects but I ordered his medical records and many of his lab results were abnormal.
I'm not sure they even know what they are looking at on the tests - outside a few diagnosable diseases.
They have what can quantitatively be said to be on the whole no idea what they are doing.
This can be proven mathematically. Essentially this goes as follows.
Jerry Vockley has shown that full-blown diseases can result from two heterozygous mutations in a closely related pathway where both are within "normal" diagnostically but the combined result is just as full-blown disease as homozygous mutations that would lead to a diagnosis.
This has received very little attention in the field.
I wrote to Vockley and I asked him this.
Is it not mathematically impossible for these not to represent >99% of such cases?
If you take the probability that enzyme A has a pathogenic mutation in both the maternal and maternal allele, and then you compare it to the probability that two different enzymes in the same pathway have their own pathogenic mutations, the odds are at least an order of magnitude higher that synergistic heterozygosity will be present. If you then expand this to two enzymes in different pathways that interact on the course of catabolizing one macronutrient to ATP, for example a fatty acid oxidation with an ETF dehydrogenase enzyme or a complex III or 4 mutation or something in CoQ10 synthesis, you now get *astronomical* odds in favor of synergistic heterozygosity.
Vockley said yes, he thinks about the math the exact same way, but it is difficult to prove causation in the cases.
But if you are trying to solve a rare problem you cannot get hung up on proving causation, you need to use a flexible model that allows you to make the best judgment, act on it, and revise as necessary.
What this shows is that most "rare diseases" will NEVER be solved, because what we are observing is that the medical diagnostic model has reached its limit to solve them. All it can accomplish now is to make trivial marginal eeking out of a new diagnosis here and there. Most "rare diseases" aren't something entirely new. They are mixed and matched pieces of existing diseases, where each piece qualifies as "normal" and thereby precludes any diagnosis.
Medicine has to EXIT its diagnostic model to help most people with severe problems who are not currently helped.
😪 My son had CVS for years, ended up in the hospital when he had episodes.
They say most children with CVS (also known as abdominal migraines) stop getting them and develop actual migraines as adults. It's more common if a mother has migraines for her child to have abdominal migraines.
I felt it might be tied to his immune defects, since his thymus organ was taken from him as a newborn during heart surgery. After that, he had chronic immune defects. I have migraines and immune problems of my own, UTI's, chronic candida, chronic EBV. I've gotten some of the infections under control but the migraines remain.
Good luck to you. 🙏
Migraines are mitochondrial dysfunction, there's abundant literature on this.
Ps the thymus organ, thymus peptides affect mitochondria. Thymosin beta 4 (Tβ4) has been shown to play a role in mitochondrial function and dynamics, particularly in relation to cell survival and tissue regeneration. It can facilitate mitochondrial transfer between cells, impacting tissue repair and regeneration, and it also plays a role in regulating apoptosis and oxidative stress within mitochondria.
Tβ4 has been shown to enhance the transfer of mitochondria from adipose-derived stem cells (ADSCs) to other cells, like adipocytes and new blood vessels, within fat grafts via tunneling nanotubes. It's linked to the upregulation of the Rac/F-actin pathway, which is crucial for forming nanotubes.
Doctors who take thymus organs from newborn babies, like what was done to my son, have been causing irreparable harm for 5 decades now.
🙏 lots of literature but no clear path to healing from my experience.
Acerola with bioflavanoids in massive doses has helped me. 35-70 grams a day. It also helps my leg cramps and vein issues but nothing completely takes it all away.
I love your page and info.
I'm sorry for all my comments.
That’s a shame. So sorry. At least there are so many in the modern health space trying To address this if you can avoid quackery. I’ve heard migraines are easy to stop with salt water and aspirin, but I can’t remember might be disinfo.
Thank you 🙏
When my child started eating around 9 months, he would vomit like crazy and would usually require IV intervention. Allergy tests came back ok, and he was diagnosed with FPIES. Many foods would trigger it like 1 cheerio, but some would not.
Chris excellent series.Not specifically a SSRI but curious on your opinion on another antidepressant,
Mirtazapine that’s been shown to help mitochondria in vivo.
A serotonergic 5- hydroxytryptamine 2/3 (5HT2/3)
receptor antagonist and
noradrenergic antidepressant, which has been used off-label for management of gastroparesis.[14] It blocks histamine H1 and serotonin 5-HTZA, 5-HT2C, and 5-HT receptors and stimulates 5-HT1A receptors
in both peripheral and the central nervous system.[15]
Stimulation of 5-HT1A receptors is
believed to be responsible for its antidepressant and anxiolytic effects,
whereas blockade of H1, 5-HT2A, and 5-HT2C receptors also contributes partly to some of its anxiolytic and sedative effects.
Mirtazapine's impact on central neural systems involved in mood regulation could have partly contributed to its orexic property.
Haven't researched it specifically, but in general I think this stuff is playing with fire for reasons already described.
🙏💞 Thank you.
I wonder what NDRI like Wellbutrin might lead to, what a person might take to avoid long term effects.
I looked up Acyl-CoA Dehydrogenase (ACAD) deficiencies. Taking L-carnitine and riboflavin (vitamin B2) are commonly supplemented. In some cases, Coenzyme Q10 and triheptanoin may also be used. Dietary modifications like restricting long-chain fats and increasing medium-chain triglycerides (MCT) are crucial.