Yes. PM me if you’d like to know more.
One would have to pay me upwards of $1billion dollars to try any of these categories of drugs. Why risk getting effed up for life when you could have amazing results from 50-100mg modafinil with no side effects and no withdrawal symptoms. Nah too dangerous to play with. Might as well get a king cobra as a pet LOL:
Yea I never really thought SSRI’s were worth it. I’ve never personally used one so if someone says it changed their lives for the better, then good for you.I could see something like Wellbutrin making more sense than an SSRI and would put that more into the modafinil category since there doesn’t seem to be much of a withdrawal risk. I actually plan on trying that to see how I feel on it.
The problem with modafinil for me at least is that I build tolerance to it rather quickly, and it causes small increases in heart rate and systolic blood pressure. Not to mention occasional insomnia.
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Well I am relatively new last 10 days or so but it is amazing. The building of tolerance I could probably see it but i think if you stay couple days off you’re good to go again. I didn’t take any yesterday just to test and took today 1/2=100mg and it’s like night and day. As far as the increases in HR and BP I honestly don’t care given how good it makes me feel, totally worth it. Plus, I happened to be in a good spot with BP I’m usually low anyway 105-110/70-75 and an increase to say 120-125/80 I don’t think I would mind. However, I haven’t experienced and increase in BP nor HR that I can notice in last 10 days (since I started).
As far as sleep, boy o boy am I ever happy I found them both (modafinil and selegiline). I’ve been tortured for last 2-3 years with barely 5 hours sleep nights and in last 2 weeks (when I started both Selegiline and modafinil) I’ve averaged over 7 hours straight. I do take them first thing in the morning though. I don’t think I’d take modafinil after AM. As far selegiline I’ve taken it couple times around 2PM and it did not adversely affect my sleep even taking it that late. Modafinil though it feels different and I’m sure it would interfere with sleep if taken in the afternoon.
fyi- I’m loading up on it nicely. Just placed an order of 600 200mgs today in addition to about 800 I already have, I think it is an absolute must have for everyone.
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Idk when it turns into a waking dream or you go in a loop, it wrecks the therapeutic effect
I don’t disendorse psychedelics, but too many people advising me to do psychedelics did contribute to me getting into “weird situations” under them and my brain is more SEBUS-prone than most
The psychedelic with the lowest downside risk is DMT, esp b/c it lasts so quickly ( it’s also so intense you don’t end up doing dumb things outside or post to social media while on it). Plus you can legally do it in Colorado
I once helped host a DMT party and it cured one person’s trauma
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I think SSRis have a bad rap because they “dull your sense-making apparatus”/constrain the brain’s dynamic repertoire and it’s overall healthier to see it all and be completely unmoved/untriggered by it which is what advanced meditation/jhana tries to do, but not everyone can meditate/jhana so the biggest ROI move is often 5-MeO-DMT (which is also short enough that people don’t do dumb/antisocial things on it like they might with psychedelics)
Saffron does work to reduce depression as my friend started it and there really was improvement in about four weeks.
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Do you mean buying them from India?
I think it does a little too. The evidence is there IMO. Been taking 30mg with breakfast and another 30mg before bed (helps with sleep too).
yes. twenty characters
It’s interesting you should mention buproprion. I am trying that now (75 mg SR - low dose) to see if it could replace or benefit modafinil. Yes, tolerance to Modafinil builds rapidly and periodic breaks for me seem to be very important. So, maybe buproprion will be beneficial? Unfortunately, from my research it could take a few weeks to see an effect, very much unlike Modafinil.
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I have had the same thought process as you and managed to get a prescription today for 150mg so I will probably start it in the next few days once I get a hold of it.
One issue is it’s contraindicated with Selegiline even thought I only take 2.5mg so I might have to stop taking that unfortunately
LukeMV, I hope you find good results with buproprion. After only one week I’ve decided to stop it. It seems to bring my mood down in the afternoons consistently and that seems contradictory to what it should do.
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Ouch, i’m hoping that doesn’t happen to me. Were you taking the XR version? What dose?
75 mg SR - low dose. Who knows why it didn’t quite work? Maybe it should have been a higher dose XL version for extended release to avoid peaks and dips. Whatever the case it’s easy to stop this low dose.
I was given 150mg XR to try
Get a mitome report? Like if you have low Complex II=>III, you may have to figure smg out…
Good question — and there’s a genuinely counterintuitive knot at the center of it that’s worth pulling apart. Let me pin down the actual data (and Masterjohn’s specific take, which I don’t want to reconstruct from vague memory).Masterjohn’s actual framing surprised me — it cuts against a belief I was carrying in from training, so let me verify the pharmacology directly before I lean on it.Now the direct-toxicity side, and what that “1 in 5,500 / devastating disease” claim of his actually refers to.Good one to dig into, because the premise most people (and, I’ll argue, Masterjohn partly) carry is subtly wrong: binding affinity ≠ functional direction. Sertraline grabs the sigma-1 receptor harder than Prozac and does roughly the opposite thing with it. And that’s only one of two independent axes. Let me separate them, because conflating them is where the whole discussion goes sideways.
Axis 1 — the sigma-1 receptor (σ1R), which is a receptor story, not a “goes to the mitochondria” story.
The affinities are settled and replicated (Narita '96, confirmed by Hashimoto’s group): fluvoxamine (Ki ≈ 17 nM) > sertraline (≈ 31.6 nM) > fluoxetine (≈ 191 nM) > escitalopram (288) > citalopram (404) ≫ paroxetine (2041 nM). So sertraline binds σ1R about six-fold tighter than fluoxetine. High confidence on those numbers.
But here’s the fork. σ1R agonism is the mito-supportive direction — σ1R lives at the MAM (mitochondria-associated ER membrane), where it acts as a Ca²⁺-sensitive chaperone stabilizing IP3R-mediated Ca²⁺ hand-off from ER to mitochondria, buffers oxidative stress, and props up BDNF/trkB signaling. Fluoxetine is an agonist here (it potentiates NGF-driven neurite outgrowth, and that’s blocked by the σ1R antagonist NE-100). Sertraline is the odd one out: these SSRIs (fluvoxamine, fluoxetine, escitalopram) appear to be sigma-1 agonists, but sertraline may act as an antagonist. It gets sharper than “may” — in the outgrowth assay sertraline itself antagonized the effect, behaving like NE-100, and in hippocampus sertraline inhibited LTP at low micromolar concentration through inverse agonism of sigma-1 receptors, blocked by an antagonist but not an agonist. There’s even a case report where fluvoxamine (σ1R agonist) and sertraline (σ1R antagonist) produced opposite effects on psychotic depression.
So on the receptor axis: Prozac occupies σ1R weakly but turns it on; Zoloft occupies it strongly but shuts it off. For mitochondria that flips the naïve expectation — the tighter-binding drug is the one removing the protective MAM signaling.
Caveat I want to flag hard, though: this is not fully settled. SSRIs are generally considered σ1R agonists, but Sigmar1-knockout studies raise the possibility they act as inverse agonists or antagonists — meaning the direction is probably concentration-, tissue-, and assay-dependent, and the “sertraline = antagonist” call is an acute-in-vitro read that may not be the whole in-vivo chronic truth. I’d put the acute antagonism at fairly-high confidence, the “this is what matters in a person on it for a year” at genuinely-uncertain.
Axis 2 — direct mitochondrial poisoning, which has basically nothing to do with sigma.
This is the physicochemistry story: both drugs are lipophilic cationic amphiphiles that partition into membranes and get concentrated by the mitochondrial membrane potential. Sertraline is the poster child. In the FDA/NCTR work, sertraline uncoupled oxidative phosphorylation, inhibited Complex I and Complex V, and induced Ca²⁺-mediated permeability transition (blocked by bongkrekic acid), and in primary hepatocytes it rapidly depleted ATP and caused LDH leakage. It’s a classic uncoupler — state-4 respiration was stimulated regardless of substrate, which is the signature of an uncoupler.
Two things keep me honest here. First, the dose gap: the concentrations used were higher than clinical plasma levels — a 400 mg dose gives a Cmax around 0.74 μM, and the toxic effects show up at low-micromolar and up. The rescue for “but it still matters” is that a membrane-potential-driven lipophilic cation concentrates in mitochondria and liver well above plasma — plausible, not proven for these specific effects. Second, and this is the tell that Axis 2 is separate from sigma: sertraline and paroxetine both drive Ca²⁺ influx and mitochondrial damage-mediated apoptosis — and paroxetine has essentially zero σ1R affinity (Ki 2041). So the direct toxicity rides on the cationic-amphiphile/Ca²⁺ machinery, not the receptor. Fluoxetine isn’t innocent (there’s data on it being directly toxic to pancreatic mitochondria, tied to diabetogenic potential), but the heavy OXPHOS-uncoupling/MPT literature clusters on sertraline. My confidence that sertraline > fluoxetine on this axis is moderate, not high — I didn’t find a clean same-assay head-to-head, and paroxetine muddies any tidy “sigma predicts toxicity” ranking.
Now Masterjohn, taken seriously — because his synthesis is actually good, and the place I diverge is specific.
His core model is the melatonin/hypoxia axis: all SSRIs block serotonin into the cell, and serotonin has to be inside the cell to support mitochondrial function — SSRIs go into the cell with ~100% efficacy and act on other receptors that activate mitochondrial stress pathways. Intramitochondrial serotonin→melatonin is a local antioxidant that helps you handle oxygen deficit. The σ1R-activating SSRIs partially rescue the intracellular serotonin pool by boosting new synthesis (tryptophan hydroxylase up), so in his framework they’re relatively favorable on that axis. His ordering is potency of SSRI activation of sigma-1 receptors: fluvoxamine > sertraline > fluoxetine > escitalopram > citalopram > paroxetine, a 52-fold spread, and he leans on the observation that citalopram and paroxetine may lower serotonin synthesis while sertraline may raise it. Separately — and this is the Janus in his own account — he calls sertraline a direct poison: in at least ~1 in 5,500 people, sertraline is such a potent mitochondrial poison that it can induce a devastating disease previously thought to be a rarer genetic disorder, and his clinical worry is switching and withdrawal — his two post-SSRI catastrophe cases were on different SSRIs, had different switches, and showed opposite effects on mitochondrial abundance, leading to his hypothesis that SSRI discontinuation is fundamentally mitochondrial dysfunction. That “unmasks latent mito disease” idea has real precedent — it’s the troglitazone-in-a-silent-mitochondrial-defect model, which is literally sitting in the reference list of the sertraline paper.
Where I part ways: he treats sertraline as a σ1R activator; the functional pharmacology says antagonist/inverse agonist. He’s essentially reading the affinity ranking (where sertraline is #2) as an activation ranking, and I think that’s a slip. If the antagonist read is right, sertraline doesn’t earn the σ1R-mediated melatonin-axis rescue he credits it with — it’d be doubly unfavorable (no compensation, or active suppression, on top of being the worst direct poison).
And a reframe I’ll flag as my own construction (moderate-low confidence, but I like it): the raised-intracellular-serotonin phenotype he attributes to “σ1R activation” might instead be the integrated stress response fingerprint — mitochondrial stress → ATF4 → tryptophan hydroxylase upregulation. He half-says this himself (“activate mitochondrial stress pathways, and part of those pathways is to increase serotonin production”). If so, sertraline showing raised serotonin synthesis isn’t evidence it’s a good σ1R agonist — it’s evidence it’s a stronger mitochondrial stressor. Same data, opposite valence. That would flip a chunk of his ordering from “activation potency” to “toxicity potency.”
So, which is actually worse for mitochondria — net? I’m honestly uncertain, and I don’t think there’s a clean single answer. Holding the hypotheses jointly:
- Sertraline clearly worse (plausible→likely, ~0.5): both axes stack against it — antagonizes the protective σ1R signaling and is the more aggressive direct uncoupler/MPT-inducer. The distinguishing evidence that would push me here: any clean demonstration that therapeutic-dose tissue/mito sertraline concentrations reach the toxic range, and confirmation the antagonism holds chronically in vivo.
- Dose/genotype/tissue-dependent, sign can flip (plausible, ~0.3): low-level σ1R agonism (Prozac) is mitohormetic/beneficial while sertraline’s toxicity only bites in susceptible people or high-accumulation tissues (liver) — i.e., “worse” is conditional, not categorical. This is closest to Masterjohn’s second-hit framing. Distinguishing evidence: mito-disease-carrier status, liver vs brain differences.
- Sigma is largely a red herring for real-world differences; physicochemistry dominates (possible, ~0.15): paroxetine (no sigma) also damages mitochondria, so the direct-accumulation axis may swamp the receptor axis clinically. Distinguishing evidence: does σ1R-knockout change the toxicity? If not, sigma’s mostly a bystander for the poisoning part.
- Reserve ~0.05 for something none of us has framed right (this literature is thin — Masterjohn’s own words: a “weak and inadequate spattering” of animal research).
Last thing, briefly and not as a lecture: essentially all the scary direct-toxicity data is in vitro and supratherapeutic, and the one intervention Masterjohn actually flags as dangerous is switching/stopping — so this is mechanism, not a green light to change anything on your own. If you’re weighing an actual decision, that’s a prescriber conversation, ideally one where the mito angle is on the table.
Want me to go deeper on any single thread — the MAM/Ca²⁺ chaperone mechanics, the ISR/ATF4 reframe, or Masterjohn’s melatonin-hypoxia model specifically?
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The lesion you’re describing — succinate→CoQ→Complex III as the choke point — is a good stress test, because the two drugs hit different parts of the chain, and the “which is worse overall” answer from last time can actually flip depending on complex-specificity. That flip is the whole question. Let me verify the complex-level data rather than reason from the overall-toxicity ranking, because those are different things.Doc 29 is the smoking gun for what Masterjohn’s “devastating disease” actually is — and it’s directly on point for your lesion. But I need one more piece: whether fluoxetine specifically touches Complex III, because that’s the fact that decides whether the answer flips.Alright — I chased the flip (the idea that fluoxetine might be the specific Complex III / CoQ hitter and therefore locally worse at your exact bottleneck), and the data mostly kills that hypothesis. So the answer isn’t the cute reversal I was hoping for. But the real answer is more interesting, because why sertraline is harder has almost nothing to do with which complex it inhibits.
First, the flip doesn’t happen — both are Complex I drugs. In the cleanest head-to-head (isolated pig-brain mitochondria, Ľupták/Fišar/Hroudová), all the antidepressants tested inhibited complex I and IV at high concentrations, and complex II+III activity was reduced by all of them except bupropion. Fluoxetine’s own profile is primarily complex I and II inhibition, and in HepG2 cells complex I-linked respiration was the most sensitive mechanism for fluoxetine-induced toxicity. Sertraline in the FDA hepatic work inhibited complex V and ANT, and behaved as an uncoupler regardless of whether the substrate fed complex I or complex II. So neither is a clean CIII inhibitor; both nick the CII+III segment a bit on top of a primary Complex I hit. Your specific weak point isn’t preferentially targeted by either. Fair-confidence on this — it’s the consistent read across several labs.
Which means the question “which is harder on a CoQ/CIII-limited person” has to be answered on the downstream consequences that matter when that segment is already the bottleneck. And there, sertraline stacks four liabilities that all bite hardest exactly in your scenario:
1. The uncoupling paradox flips sign based on where your lesion sits — and yours is in the wrong place. This is the part I find most worth saying. Mild uncoupling is normally antioxidant (Skulachev): drop the membrane potential, the Q pool oxidizes, ROS falls. If your problem were a hyperpolarized/reverse-electron-transport ROS phenotype, sertraline’s uncoupling would arguably help you. But your block is downstream at CoQ→CIII. Uncoupling can’t pull electrons through a downstream jam, so you get almost none of the ROS relief and the full ATP cost — an already-marginal membrane potential collapsing with no compensation. Fluoxetine is the weaker uncoupler of the two (its ATP interference is more via embedding in the inner-membrane lipid bilayer and inhibiting electron transport and F1F0-ATPase). So the single drug-property that’s most double-edged here lands on the bad edge specifically for your lesion.
2. Sertraline sensitizes the permeability transition pore — the exact death mode a CIII-deficient cell is nearest to. When succinate-Q reductase activity is suppressed (which is what CoQ deficiency or CIII impairment does), electrons stall and leak from the complex-II flavin semiquinone to oxygen, generating superoxide. So you’re already a high-ROS, MPT-primed cell. Sertraline then induces Ca²⁺-mediated permeability transition, prevented by bongkrekic acid, via ANT — it’s actively pushing on the trigger you’re closest to. Fluoxetine’s σ1R agonism (from last turn) runs the other way: it tends to stabilize ER→mito Ca²⁺ handling. This is probably the most important single differentiator, and it’s a mechanism, not a correlation.
3. Sertraline has a named acquired version of your disease; I couldn’t find fluoxetine’s equivalent. This turns out to be what Masterjohn’s “1-in-5,500 devastating disease” almost certainly refers to: sertraline-associated lipid storage myopathy, described as an acquired mitochondrial disorder with respiratory chain deficiency, showing reduced complex II (SDH) and complex IV (COX) staining. Read that against your stipulated lesion — the drug’s real-world idiosyncratic phenotype is Complex II reduction. Giving it to someone already CII/CoQ-limited is adding a second hit to the same lesion, which is precisely the troglitazone-style “unmask the silent mitochondrial defect” model. This is the part of Masterjohn’s analysis I think is strongest (as opposed to his σ1R-direction claim, which I still think is backwards — he treats sertraline as a σ1R activator; the functional pharmacology says antagonist/inverse agonist, and if that’s right, sertraline also fails to give you the hypoxia-response support a CIII-limited cell needs more than a healthy one). Caveat I’ll flag honestly: absence of a “fluoxetine myopathy” literature isn’t proof fluoxetine is clean — it may just be less reported. So treat #3 as suggestive, not settled.
4. The whole thing is dose-gated, and that cuts toward “don’t panic.” Every complex-inhibition number above is at 50–100 µM, much higher than therapeutic plasma concentrations — often 2- to 40-fold or more above serum levels. At real plasma levels, direct chain inhibition by either drug is probably minimal; the mitochondrial-accumulation argument (lipophilic cations concentrating down the membrane potential) plus the acquired-myopathy cases show it can matter in susceptible people, but that’s the rare tail, not the default.
So, holding the hypotheses jointly rather than pretending I’m sure:
Sertraline is the harder one for this lesion — plausible-to-likely, call it ~0.55. Four independent vectors converge (uncoupling-in-the-wrong-place, MPT sensitization, the CII-deficient acquired myopothy, likely σ1R antagonism), and convergence from independent mechanisms is worth more than any one of them. What would move me off it: if the σ1R “antagonist” call is wrong (Masterjohn’s read), sertraline loses one demerit.
Fluoxetine could be the harder one — plausible, ~0.25. The counter-case is real: norfluoxetine caused the greatest complex I inhibition among the drugs in one dataset, and fluoxetine/norfluoxetine has a very long half-life (weeks) — a slow-clearing Complex I inhibitor that also embeds in the inner membrane could impair CoQ mobility and supercomplex/CIII function more than an acute assay reveals. If your deficit is truly CoQ-carrier-centric rather than CIII-protein-centric, membrane-disrupting persistence might matter more than acute MPT risk. (Note the genuine Janus: more Complex I inhibition is bad for ATP but arguably good for ROS in a downstream-blocked cell — fewer electrons piling up behind the jam. So fluoxetine’s stronger CI hit is itself two-faced.)
They’re roughly equivalent at real doses; your metabolic state and cofactor status dominate the drug choice — plausible, ~0.2. RC-deficient cells are rescued by ample glucose but killed by the same inhibitors when reliant on oxidative substrate like glutamine. Translation: a glycolytically-buffered, well-fed you tolerates either; a fasted / ketogenic / high-oxidative-demand you with a CoQ deficit is exposed to whichever is more mitotoxic. CoQ10 status and riboflavin (the CII flavin cofactor — the very site leaking superoxide) may swing your vulnerability more than sertraline-vs-fluoxetine does.
Reserve ~0.05–0.1 for something none of this frames right — tissue-specific reversals (the ranking could differ between brain, muscle, liver depending on which tissue is symptomatic), a pharmacogenomic wrinkle, a metabolite I’m underweighting.
Distinguishing evidence that would actually resolve it, if you could get it: steady-state mitochondrial accumulation ratios for each drug in your symptomatic tissue (settles the dose caveat); cardiolipin/supercomplex integrity data per drug (settles whether fluoxetine’s membrane effect hits CIII assembly); and whether the σ1R antagonism holds chronically in vivo (settles one of sertraline’s four demerits).
I’ll flag I’m constructing a fairly confident “sertraline” narrative here, and the honest cap on it is: the mechanistic convergence is real, but it’s built on supratherapeutic in-vitro data plus a rare clinical phenotype, so it’s a lean, not a verdict. And the one maneuver the actual case reports flag as most dangerous is switching SSRIs — so if this is personal and not just curiosity, the mechanism points one way but the decision (especially any change) is genuinely one to individualize with someone who has your actual mito workup in front of them; I’m reasoning from biochemistry, not your labs.
Want me to go down the CoQ-carrier-vs-CIII-protein distinction? Because which of those two your “CoQ-ish” deficit actually is would meaningfully shift the sertraline/fluoxetine weighting — they’re not the same lesion even though they share the segment.
- Fluoxetine
Strong autophagy/AMPK/mTOR/ULK literature, plus FIASMA behavior. It can induce autophagy through the AMPK/mTOR/ULK axis in several cancer models.
Yes. Very plausibly. Prozac does this. Prozac = fluoxetine, an SSRI, but fluoxetine is also a FIASMA, meaning it functionally inhibits acid sphingomyelinase / ASM. So the “SSRI = serotonin reuptake blocker, end of story” model is probably too cartoonish, because apparently the brain did not consult the intro psych textbook.
The best current answer is:
Some antidepressant effects may be mediated by ASM/ceramide suppression, especially downstream plasticity/autophagy/neurogenesis effects. But this is not proven to be the whole clinical effect in humans.The strong preclinical claim
A key 2013 Nature Medicine paper argued that the acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs. The authors tested antidepressants including amitriptyline and fluoxetine, and the model was basically:
depression/stress state → ↑ ASM activity → ↑ ceramide → impaired hippocampal neurogenesis / neuronal survival → depression-like behavior amitriptyline or fluoxetine → ↓ ASM activity → ↓ ceramide burden → restored neurogenesis/survival → antidepressant-like behavioral effectsFollow-up reviews summarize the result as evidence that antidepressant effects of amitriptyline, fluoxetine, and fendiline were mediated by the ASM/ceramide system rather than merely by acute monoamine reuptake effects. (PubMed)
Prozac specifically
Fluoxetine is officially an SSRI, approved for major depressive disorder and other indications, so serotonin transporter blockade is real, not fake. The FDA label describes fluoxetine as a selective serotonin reuptake inhibitor indicated for MDD, OCD, bulimia, panic disorder, etc. (FDA Access Data)
But fluoxetine also shows ASM/FIASMA activity. Multiple papers and reviews report that therapeutic concentrations of fluoxetine and amitriptyline reduce ASM activity and alter sphingomyelin/ceramide signaling. (Wiley Online Library)
So fluoxetine is doing at least two conceptually different things:
acute: fluoxetine → blocks SERT → ↑ synaptic serotonin slower: fluoxetine → inhibits ASM → sphingomyelin/ceramide remodeling → autophagy / hippocampal plasticity / stress-response changesThat slower part is interesting because antidepressants often have delayed clinical effects, while SERT occupancy happens fast. So the ASM/autophagy/neuroplasticity story fits the “why does this take weeks?” mystery better than “serotonin instantly rises and then everyone feels better,” which was always suspiciously neat.
The ULK1/autophagy connection
A 2018 Molecular Psychiatry paper found that amitriptyline and fluoxetine induced autophagy in hippocampal neurons, but only after about 2 weeks, not after 5 days. The proposed sequence was:
fluoxetine / amitriptyline → ↓ ASM activity → ↑ sphingomyelin in lysosomes + Golgi → ↑ ceramide in ER → PP2A activation → ULK activation → Beclin + VPS34 activation → ↑ p62 and LC3B → autophagy inductionThat is the beautiful cursed part: ASM inhibition may lower one ceramide pool while raising another compartmental ceramide pool that activates autophagy. Cells: apparently tiny lipid accounting fraud machines. (Nature)
Human evidence: suggestive, not airtight
There is human evidence that the ASM/ceramide axis is relevant to depression, but it is not yet “we can prescribe based on ASM labs” level.
A 2005 prospective case-control study found higher acid sphingomyelinase activity in peripheral blood mononuclear cells of patients with major depression, and ASM activity correlated with depression severity in that small sample. (PubMed)
A 2022 study reported that plasma ceramide levels correlate with major depressive disorder severity, and in mice, neutralizing ceramide could reduce depressive behavior. (JBC)
But serum/secretory ASM results are mixed: one 2019 study found serum secretory ASM was not simply lower in medicated/remitted groups, though changes in S-ASM during treatment related to symptom improvement and severity. (PMC)
So the human version is:
ASM/ceramide axis appears associated with depression severity and may track response in some contexts, but it is not yet a clean clinical biomarker.Why this could be therapeutic
ASM/ceramide overactivation can impair several things depression cares about:
↑ ASM / ceramide → worse membrane signaling → less hippocampal neurogenesis → more inflammatory/stress signaling → impaired neuronal survival/plasticity → depressive-like phenotypesThen FIASMA antidepressants may do:
↓ ASM → normalize ceramide signaling → restore hippocampal plasticity → induce autophagy via ULK1/Beclin/VPS34 → improve stress resilienceThis would make fluoxetine not just a serotonin drug, but a serotonin + lysosomal lipid signaling + autophagy/plasticity drug. Which is messy, but also much more believable.
The punchline
Yes: fluoxetine/Prozac reduces ASM activity, and there is fairly strong animal/cellular evidence that this contributes to antidepressant-like effects.
But in humans, I’d phrase it as:
ASM inhibition is a plausible downstream/parallel mechanism of some antidepressants, especially fluoxetine and tricyclics, but not the sole established clinical mechanism.My ranking of confidence:
Claim Confidence Fluoxetine/Prozac inhibits ASM function High ASM/ceramide affects depression-like behavior in animals High ASM inhibition contributes to antidepressant-like effects in mice High-ish ASM inhibition explains part of human antidepressant response Plausible, not proven ASM labs can guide antidepressant choice today No, humanity has not earned that tool yet So yes, Prozac is not merely “serotonin go brrr.” It may also be turning down ASM/ceramide stress signaling and shifting hippocampal autophagy/plasticity through ULK1. Tiny lysosomal lipid goblin, major mood implications.
