Endotoxin (LPS) May Cause Depression / Anhedonia

Discussion in 'Scientific Studies' started by haidut, May 28, 2019.

  1. haidut

    haidut Member

    Joined:
    Mar 18, 2013
    Messages:
    16,613
    Gender:
    Male
    Location:
    USA / Europe
    As many readers know, anhedonia is one of the most pernicious aspects of clinical depression. It is present in other mental health conditions but is most pronounced and severe in clinical unipolar depression. It is also especially resistant to treatment and many doctors simply accept it as something that current drugs cannot address and focus on improving overall quality of life for the patient as much as current pharma options allow. The sad reality is that despite the well-known link between anhedonia and low dopamine (and thus high-serotonin), nobody has made the suggestion (at last officially) that serotonin may actually be a cause of depression. No suggestions have been made about treating anhedonia with dopamine agonists and/or serotonin antagonists despite the mountain of evidence from animal studies.
    Be that as it may, the study below demonstrates the endotoxin can directly cause depression and anhedonia, by acting on the TLR receptors and thus increasing inflammation. While the study does not mention it, this also directly implicates serotonin as a causal factor in depression as endotoxin manifests most of its negative effects on health by activating serotonin synthesis in the gut and by increasing NO synthesis/release. It is impossible to activate the TLR4 receptors the study below discusses without also increasing serotonin/NO. I suppose it would be too brave for the authors to call serotonin out for what it is, but at the very least the role of endotoxin in chronic conditions is starting to get recognized, and I'd take this as a good start. The study does claim that the anhedonic and depressive effects of endotoxin affect mostly females, but I am not convinced males are exempt. I think males are simply more resilient initially due to their higher testosterone levels, which itself has potent antidepressant effects. On the other hand, the higher estrogen levels in women predispose to depression and females' estrogen levels are more sensitive to endotoxin assaults. This likely explains the gender differences seen in the studies, and when these differences between genders dwindle in older age, endotoxin becomes just as strong depressive and anhedonic agent for males as well. As such, blocking TLR4 may be a viable treatment for anhedonia/depression and studies with TLR4 antagonists like naltrexone, amitriptyline, cyproheptadine, progesterone, vitamin D/A, riboflavin, have all demonstrated antidepressant effects further corroborating the findings of the study below.

    Sex Differences in the Relationship Between Inflammation and Reward Sensitivity: A Randomized Controlled Trial of Endotoxin - ScienceDirect
    Brain study may explain why depression is more common in women

    "...Anhedonia is one of the hallmarks of major depressive disorder. Anhedonia describes the inability to derive joy or pleasure from activities that used to feel enjoyable. On a neurological level, anhedonia presents itself as reduced activity in the brain's reward processing area, called the ventral striatum."

    "...Prof. Eisenberger and colleagues administered either a low dose of an endotoxin — in order to induce inflammation — or a placebo to depression-free men and women. In total, the study included 115 participants, 69 of whom were female. The researchers randomly assigned the participants to either the control/placebo group or the low-dose endotoxin group."

    "...The results revealed that the endotoxin reduced the activity of the reward-processing ventral striatum. However, the researchers noticed that this effect differed according to sex. "Specifically," report Prof. Eisenberger and colleagues, "in female participants, endotoxin (vs. placebo) led to decreased [ventral striatum] activity in anticipation of reward, but this effect was not present in male participants." Also, these decreases in the activity of the ventral striatum "were related to increases in inflammation for female but not male participants."
     
  2. Lokzo

    Lokzo Member

    Joined:
    Mar 26, 2016
    Messages:
    1,239
    Gender:
    Male
    Occupation:
    Naturopath
    Location:
    Melbourne
    Outstanding presentation @haidut
     
  3. Momado965

    Momado965 Member

    Joined:
    Aug 28, 2016
    Messages:
    754
    Gender:
    Male
    Whats a reasonable dose of cypro and for how long to treat Anhedonia?
     
  4. Lokzo

    Lokzo Member

    Joined:
    Mar 26, 2016
    Messages:
    1,239
    Gender:
    Male
    Occupation:
    Naturopath
    Location:
    Melbourne
    I believe @haidut suggests no more than 1mg, twice per week.
     
  5. Jem Oz

    Jem Oz Member

    Joined:
    Jun 13, 2016
    Messages:
    169
    Gender:
    Male
    @Lokzo I'd be surprised if @haidut recommended such a low dose. Maybe for 'maintenance' long term? From memory he took MUCH higher amounts over a significant period of time. If you have overt issues that need addressing, I think you'd need a lot more cypro, at least for a month or so.
     
  6. Momado965

    Momado965 Member

    Joined:
    Aug 28, 2016
    Messages:
    754
    Gender:
    Male
    @haidut What was your high dose of cypro?
     
  7. Vladimir Erfán

    Vladimir Erfán Member

    Joined:
    Apr 24, 2017
    Messages:
    46
    Gender:
    Male
    Haidut recommended 1-2mg daily, because in higher dosages, according to Ray Peat, it elevates liver enzymes for unknown reasons. The problem with cyproheptadine is that it tanks your dopamine aswell, which makes you anhedonic in it's own way (for me atleast).
     
  8. OP
    haidut

    haidut Member

    Joined:
    Mar 18, 2013
    Messages:
    16,613
    Gender:
    Male
    Location:
    USA / Europe
    If used chronically, I would use no more than 2mg daily and then do a liver panel test at the end of the first month of usage. If liver enzymes are sufficiently elevated (which for some people cypro can do) then drop to 1mg maybe 2-3 times a week. If they are not, then higher doses can probably be used.
     
  9. Kartoffel

    Kartoffel Member

    Joined:
    Sep 29, 2017
    Messages:
    1,199
    Gender:
    Male
    Have you ever personally seen that happen in some people using such low doses of cypro? I know 4 people (including myself) that have used between 6-20mg daily for periods lasting longer than two months, and none of us had any adverse effects or alarming blood results. The studies looking at children have also never reported elevated liver enzymes.
     
  10. Lokzo

    Lokzo Member

    Joined:
    Mar 26, 2016
    Messages:
    1,239
    Gender:
    Male
    Occupation:
    Naturopath
    Location:
    Melbourne
    Did you put on weight during that period??

    Also, have you had your fasting insulin measured?
     
  11. Kartoffel

    Kartoffel Member

    Joined:
    Sep 29, 2017
    Messages:
    1,199
    Gender:
    Male
    No and no.
     
  12. Lokzo

    Lokzo Member

    Joined:
    Mar 26, 2016
    Messages:
    1,239
    Gender:
    Male
    Occupation:
    Naturopath
    Location:
    Melbourne
    What other drugs/supps were you combining with Cypro during that time?
     
  13. Kartoffel

    Kartoffel Member

    Joined:
    Sep 29, 2017
    Messages:
    1,199
    Gender:
    Male
    None, besides a few milligrams of progesterone occasionally, and about 5-8g of glycine every day. I still take 2-6mg every day depending on how I feel. 2mg right before bed makes me sleep through the night without any interruption almost every time - something I have never had before with anything else I tried. My sleep wasn't terrible before, but getting 8 hours of sleep without waking consistently is something I have never had before, not even as kid i believe.
     
  14. Lokzo

    Lokzo Member

    Joined:
    Mar 26, 2016
    Messages:
    1,239
    Gender:
    Male
    Occupation:
    Naturopath
    Location:
    Melbourne

    Wow, thats pretty amazing!! I am boosting Progesterone with Cistanche extract. Herba Cistanche (Rou Cong-Rong): One of the Best Pharmaceutical Gifts of Traditional Chinese Medicine

    That sleep quality is amazing, I agree, every time I use Cypro, my deep sleep stays in the 2hr20mins range, and REM Sleep below 1 hour.

    Amazing how it barely has any tolerance for you too.

    Would you say that it has a positive effect on libido during dosing or after using it?
     
  15. Kartoffel

    Kartoffel Member

    Joined:
    Sep 29, 2017
    Messages:
    1,199
    Gender:
    Male
    I think the stupefying effect disappears very quickly. The first time I took it, 0.5mg knocked me out completely and I was pretty non-functional for a day or two. But after that it has given be nothing but calm energy. No anhedonia or other negative effects I can think of. It's definitely good for libido, which makes sense since serotonin, cortisol, and prolactin are the main antagonists of testosterone. It definitely lowers the first two, and most studies suggest that it has direct anti-prolactin properties, too.
     
  16. OP
    haidut

    haidut Member

    Joined:
    Mar 18, 2013
    Messages:
    16,613
    Gender:
    Male
    Location:
    USA / Europe
    There are multiple reports of forum users experiencing this actually, even from low doses. Several women reported this from 2mg daily. I seem to remember either @Blossom or @thebigpeatowski were some who had those side effects. I also got (mildly) elevated liver enzymes when I was using 8mg-12mg cypro daily back in my early Peat days when I had high cortisol/prolactin. And yes, my liver enzymes were normal before starting cypro. It does not happen in everybody, that's why I suggested starting low, testing liver and everything seems fine then maybe increasing the dose. Finally, several people asked Peat over email about potential liver issues with cypro and he told them it may cause issues with BOTH gallbladder and liver. I think those emails are also posted here somewhere. But in typical Peat fashion, he has told different things to others including the latest statement that cypro is safe even in high doses. Maybe he does not consider the enzyme elevation to be clinically relevant??
    Cyproheptadine
    Cyproheptadine-Induced Acute Liver Failure
    https://www.researchgate.net/publication/269643748_Cyproheptadine_for_central_hypertension

    Here is one email he sent to a person who was concerned about 4mg cypro changing a male's urine color almost immediately.

    "RP: ...Large amounts of cyproheptadine might affect the gallbladder or ducts in a way that could increase bilirubin, making the urine brown. I have found that less than one milligram of it can be very helpful; I think it should be taken for only a few days at a time. Thyroid, progesterone, and maybe small amounts of DHEA or testosterone (around 2 to 4 mg/day) should help to reduce inflammation, improve immunity and normalize the ureters."
     
  17. Lokzo

    Lokzo Member

    Joined:
    Mar 26, 2016
    Messages:
    1,239
    Gender:
    Male
    Occupation:
    Naturopath
    Location:
    Melbourne

    The amnesic/stupefying properties definitely do fade, from my experiments with it. The initial dose was pretty intense, made me so fatigued and dysfunctional too.

    But I agree, eventually everything smoothens out, and it leaves you feeling way better the more you take it.

    The issue with me is that my cortisol levels are already TANKED... so low. SO cypro acutely makes me worse, but on the rebound makes me feel amazing.
     
  18. Lokzo

    Lokzo Member

    Joined:
    Mar 26, 2016
    Messages:
    1,239
    Gender:
    Male
    Occupation:
    Naturopath
    Location:
    Melbourne
    I heard you talking that in your early days, you had symptoms of MS.. muscle weakness, tingling, etc.

    But at that time you had ultra high cortisol and prolactin....

    Were you training a lot back then?

    Weird, because I have LOW cortisol, LOW aldosterone, LOW prolactin, Hight Free T, high DHT, HIGH T3 and T4, 0.9 TSH, but exhibit muscle weakness, tingling and reduced pumps/feeling as well. So anything that lowers cortisol actually makes me feel much weaker and worse. So hunting something to replicate what licorice does, because licorice really helps my blood pressure/muscle weakness.
     
  19. Kartoffel

    Kartoffel Member

    Joined:
    Sep 29, 2017
    Messages:
    1,199
    Gender:
    Male
    Thanks. Case reports should always be taken with a grain of salt. I don't want to downplay potential adverse effects of cypro, I just down see any evidence for them. Elevated liver enzymes are not necessarily a sign of damage, and there are several case reports of people recovering from advanced HCC with cypro.Years ago, when I asked Peat about his advice for a relative with liver cancer he mentioned cyproheptadine specifically (2mg).

    "Besides those, I would include an antibiotic to reduce intestinal bacteria, and captopril, a small amount of cyproheptadine (2mg) or ketotifen or possibly other antihistamines, and some lidocaine, either orally or transdermally (ointment or patch). I’ve known a few people (and dogs and cats) that lived a long time with liver cancer, just using progesterone."​
     
  20. yerrag

    yerrag Member

    Joined:
    Mar 29, 2016
    Messages:
    4,337
    Gender:
    Male
    Location:
    Manila
    I'm glad I had some cypro on hand. The night before, I just couldn't sleep and couldn't understand what was going on. I used 6 drops (3 mg) of cypro and also took benadryl. I slept well that night, and only woke up once to pee. Until that day, it didn't occur to me to consider increased serotonin as a cause. But looking up some searches on this forum, I was able to make the connection between endotoxins and serotonin.

    Over these past 6 months, I've increased my girth from 29 to 32 inches, and my weight has ballooned from 145 to 165 lbs. I was taking this lightly as in the past when this had happened, my weight and waistline would just swing back like a pendulum easily, and in the past I've not gotten this large. I also thought my hair has thinned some more, and that my libido has tanked. For the first time, I had lost interest in sex. I thought then that maybe the time has come when I should accept that I'm on the tanking phase already. Most importantly, I began to lose the zest, the joy of living. I was beginning to feel myself like a cow on pasture.

    It was only lately that I began to put things together that would seem to make sense of it all. About six months ago, I began to take proteolytic enzymes hoping that they would lyse the plaque in my arterial vascular network, and that as a result it would lower my blood pressure. Against hope, I was not seeing the results I expected. My blood pressure didn't go down. It actually went up. I kept trying all sort of supplements, including doxycyline. It was hard to make any definitive conclusions as to what worked and what didn't. To make a long story short, it was all in vain. The silver lining here is that it made me understand the complexity in attempting to self-heal. There is no such thing as the shortest distance between a straight line from point a to b being the shortest distance here. Another thing I learned is the power of endotoxins. I thought lysing plaque was the straight line, but what turned the straight line into a maze was endotoxins. As plaque was being lysed by proteolytic enzymes, the endotoxin component of plaque was being released to my blood stream at a strong and steady rate. I couldn't see what's going on, but I could feel the effects. I was urinating every 45 minutes during the day, and at night I was waking up to pee so often I couldn't get any semblance of a decent sleep. As I said before, my blood pressure went further up.

    I have to give my respect to endotoxins after this incident. Otherwise, I would end up as a carcass just as a drunkard would on a placid river, out of disrespect for the power of a river. I now have a firsthand account of the power of endotoxins. And now I understand why Ray Peat has been so annoyingly repetitive in cautioning against endotoxins, even to the point of omitting mention of bacteria. Endotoxins are toxins, and the damage they do can't be underestimated. They are frequently there to accompany sick patients to death - in the form of sepsis. I used to think sepsis was a case of bacterial or viral infection, but now I believe it more to be the case of endotoxins, ready to strike and deal the final blow. I could be wrong, but when I read about sepsis, there is always enough ambiguity written to leave enough doubt as to whether it was caused by infection or by endotoxins.

    Now, I'm having to use cyproheptadine and looking for more serotonin antagonists to use if I were to resume my use of enzymes to lyse plaque. Perhaps I'll have to resort to cycling the use of proteolytic enzymes. I'm also looking at buying an ionizer, so that negative ions can be used to produce superoxides that would oxidize the serotonin as they are transported attached to platelets when they reach the lungs.

    What other ways can you guys suggest to add to ways to counter serotonin? As well as endotoxins?
     
Loading...