DaveFoster
Member
So, let's talk anti-histamines and anti-cholinergic drugs.
Obviously, they reduce the short-term memory capabilities of the individual, but as purported by haidut, such executive capacities are enhanced through the actions of estrogen, for example, so they are a short-term gain at the expense of long-term structural integrity.
Let's go over the drugs that reduce both histamine, acetylcholine, and ideally other stress hormones, such as cortisol, prolactin, TSH, serotonin, and estrogen, among others.
Cyproheptadine
Here's a viable option, as cyproheptadine is used to treat a myriad of conditions, and seems to suppress 'suppress prolactin, growth hormone, aldosterone, ACTH, TSH, and cortisol'; win, win, win, win, win, win, and win.
However, cyproheptadine also acts an antagonist to D3 receptors; an undesirable side-effect. This can leave one without adequate focus, concentration, or energy due to redcued dopaminergic transmission. This may be offset by supplementing a ergot-derivative, such as LSD, lisuride, bromocriptine, or the most ideal ergot drug, hydergine.
Additionally, cyproheptadine seems to counteract the negative cardiovascular effects of ergot-derivatives. Therefore, it may enhance the safety and efficacy of all ergot-derivatives.
So, let's look at some alternative drugs similar to cyproheptadine to that do not antagonize D3 receptors.
Mianserin
Similar to cyproheptadine, mianserin extends lifespan. Peat has mentioned the mianserin also reduces aggressive behavior, which seems to fall in line with cyproheptadine's sedative effects. Like cyproheptadine, mainserin also may be effective in treating autism.
Mianserin, but not ritanserin, increases extracellular dopamine concentrations in the prefrontal cortex.
Mianserin also activates k-opioid receptors and acts a partial opioid agonist. By comparison, estrogen also acts an agonist to mu and kappa opioid receptors. This is likely an undesirable effect of mianserin.
Roads @ drugs-forum.com
Mirtazapine
As previously metnioned, mirtazapine does not act as an NRI like mianserin. I am currently unaware of Peat's opinion of norepinephrine, but I do know that he is against excessive epinephrine (adrenaline.)
Ray Peat:
It seems that Peat is in favor of lower norepinephrine (noradrenaline) and epinehprine (adrenaline) concentrations, so it seems that mirtazapine is superior in this regard.
Ketanserin
Ketanserin also effectively treats autism.
As previously mentioned by Peat, ketanserin inhibits noradrenaline responses.
Of the drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT antagonist, lacks [serotonergic] agonist activity and has alpha-adrenoceptor blocking activity.
Such_Saturation
Ritanserin
Pergolide, along with ondanesteron or ketanserin, but not mirtazapine, revesrses long-term methamphetamine sensitization. So for all you meth heads out there, this is the drug combination for you.
Ritanserin improves sleep quality. Doses are 5-10 mg for this effect.
Ritanserin blocks dopamine re-uptake in the rat frontal cortex, similar to cocaine.
Ritanserin seems to provide a more stimulating option than ketanserin.
Flibanserin
Flibanserin seems to raise dopamine and norepinephrine concentrations, while lowering serotonin. This reminds me of Wellbutrin. Both significantly enhance the sex drive.
Famotidine
Famotidine lowers PTH quite significantly, improves glucose metabolism, is a CA inhibitor, is hepatoprotective, promotes wound healing, and plays a role in treating schizophrenia, autism, Parkinson's, and protects against radiation, and sand scavenges for nitric oxide.
Diphenhydramine
I remember hearing that diphenhydramine causes a shift in memorization that prioritizes positive remembrances, and I have personally found this to be accurate, but I'm unable to find a source, so this remains anecdotal. Also allow me to note that, despite the initial grogginess and lack of performance brought on by cyproheptadine, my memory and ability to reason critically substantially improved. Thyroid also likely assisted in this, probably to a greater extent.
Diphenhydramine has weak serotonin binding affinities at higher doses, whih makes it behave like a low-dose SSRI; not ideal whatsoever. Additionally, excipients tend to be pretty awful with OTC products. Here's an interesting study for the sedation of diphenhydramine to wear off after 4 days.
L-Theanine
Apparently, theanine does lower histamine levels. It also lowers serotonin and raises dopamine.
Theanine both raises dopamine and lowers serotonin. It also lowers cortisol. The nootropic effects of l-theanine, along with the gabergic and anti-cortisol effects makes it the perfect complement to caffeine for any user. It's one of the most advantageous substances on earth due to it's extremely low toxicity.
Here's a study showing increased GABA concentrations, there also may be a risk for increased serotonin levels.
Chlorcyclizine
Here's some information on alternative anti-serotonin drugs, including chlorocyclizine. As said by haidut, clemastine seems particularly interesting for its anti-serotonergic proroperties. I can't find much information of chlorocyclizine and dopaminergic activity.
Some wisdom by haidut:
Obviously, they reduce the short-term memory capabilities of the individual, but as purported by haidut, such executive capacities are enhanced through the actions of estrogen, for example, so they are a short-term gain at the expense of long-term structural integrity.
Let's go over the drugs that reduce both histamine, acetylcholine, and ideally other stress hormones, such as cortisol, prolactin, TSH, serotonin, and estrogen, among others.
Cyproheptadine
Here's a viable option, as cyproheptadine is used to treat a myriad of conditions, and seems to suppress 'suppress prolactin, growth hormone, aldosterone, ACTH, TSH, and cortisol'; win, win, win, win, win, win, and win.
However, cyproheptadine also acts an antagonist to D3 receptors; an undesirable side-effect. This can leave one without adequate focus, concentration, or energy due to redcued dopaminergic transmission. This may be offset by supplementing a ergot-derivative, such as LSD, lisuride, bromocriptine, or the most ideal ergot drug, hydergine.
Additionally, cyproheptadine seems to counteract the negative cardiovascular effects of ergot-derivatives. Therefore, it may enhance the safety and efficacy of all ergot-derivatives.
So, let's look at some alternative drugs similar to cyproheptadine to that do not antagonize D3 receptors.
Mianserin
Similar to cyproheptadine, mianserin extends lifespan. Peat has mentioned the mianserin also reduces aggressive behavior, which seems to fall in line with cyproheptadine's sedative effects. Like cyproheptadine, mainserin also may be effective in treating autism.
Mianserin, but not ritanserin, increases extracellular dopamine concentrations in the prefrontal cortex.
Mianserin also activates k-opioid receptors and acts a partial opioid agonist. By comparison, estrogen also acts an agonist to mu and kappa opioid receptors. This is likely an undesirable effect of mianserin.
Roads @ drugs-forum.com
Further evidence for mianserin as increasing noradrenaline concentrations.
Mirtazapine
As previously metnioned, mirtazapine does not act as an NRI like mianserin. I am currently unaware of Peat's opinion of norepinephrine, but I do know that he is against excessive epinephrine (adrenaline.)
Ray Peat:
It seems that Peat is in favor of lower norepinephrine (noradrenaline) and epinehprine (adrenaline) concentrations, so it seems that mirtazapine is superior in this regard.
Ketanserin
Ketanserin also effectively treats autism.
As previously mentioned by Peat, ketanserin inhibits noradrenaline responses.
Of the drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT antagonist, lacks [serotonergic] agonist activity and has alpha-adrenoceptor blocking activity.
Such_Saturation
Moderate and severe toxicity may benefit from serotonin
receptor 2a (5-HT2A) blockade with cyproheptadine tablets
or parenteral chlorpromazine most often cited. There
are, however, also other potent 5-HT2A antagonists such
as olanzapine and ketanserin.12,13 Ketanserin does have
the benefit of intravenous availability and a lack of effect
on dopamine receptors which makes it a safer choice if
neuroleptic malignant syndrome cannot be excluded.
Ritanserin
Pergolide, along with ondanesteron or ketanserin, but not mirtazapine, revesrses long-term methamphetamine sensitization. So for all you meth heads out there, this is the drug combination for you.
Ritanserin improves sleep quality. Doses are 5-10 mg for this effect.
Ritanserin blocks dopamine re-uptake in the rat frontal cortex, similar to cocaine.
Ritanserin seems to provide a more stimulating option than ketanserin.
Flibanserin
Flibanserin seems to raise dopamine and norepinephrine concentrations, while lowering serotonin. This reminds me of Wellbutrin. Both significantly enhance the sex drive.
Famotidine
Famotidine lowers PTH quite significantly, improves glucose metabolism, is a CA inhibitor, is hepatoprotective, promotes wound healing, and plays a role in treating schizophrenia, autism, Parkinson's, and protects against radiation, and sand scavenges for nitric oxide.
Diphenhydramine
I remember hearing that diphenhydramine causes a shift in memorization that prioritizes positive remembrances, and I have personally found this to be accurate, but I'm unable to find a source, so this remains anecdotal. Also allow me to note that, despite the initial grogginess and lack of performance brought on by cyproheptadine, my memory and ability to reason critically substantially improved. Thyroid also likely assisted in this, probably to a greater extent.
Diphenhydramine has weak serotonin binding affinities at higher doses, whih makes it behave like a low-dose SSRI; not ideal whatsoever. Additionally, excipients tend to be pretty awful with OTC products. Here's an interesting study for the sedation of diphenhydramine to wear off after 4 days.
L-Theanine
Apparently, theanine does lower histamine levels. It also lowers serotonin and raises dopamine.
Theanine both raises dopamine and lowers serotonin. It also lowers cortisol. The nootropic effects of l-theanine, along with the gabergic and anti-cortisol effects makes it the perfect complement to caffeine for any user. It's one of the most advantageous substances on earth due to it's extremely low toxicity.
Here's a study showing increased GABA concentrations, there also may be a risk for increased serotonin levels.
Chlorcyclizine
Here's some information on alternative anti-serotonin drugs, including chlorocyclizine. As said by haidut, clemastine seems particularly interesting for its anti-serotonergic proroperties. I can't find much information of chlorocyclizine and dopaminergic activity.
Some wisdom by haidut:
I guess I have to apologize if my threads seem like recommendations on something. I usually post stuff that shows how one method, nutrient, supplement, or drug consistent with Peat's writings has been studied IN ISOLATION by some scientists and they have found beneficial or harmful effect. But that's how science works nowadays - trying thing in isolation to determine as much as possible the effects of that specific thing. So, if the study on how protein diet showed reduced NAFLD that great. It does not imply that it WILL work for you but that it MAY be helpful. Many factors come into play when determining if something will affect you well or not. For instance, if you have not been running for stress hormones for a long time (which usually means you are under 30 years old) then high protein diet will probably have very beneficial effect on your liver IF you had NAFLD. But if you are young(er) and healthier then you probably don't have NAFLD to start with.
Therein lies the trick with Peat's approach - everything affects everything else and depends on everything else. So, how do you go about solving it all? I think some of his basic recommendations are very helpful. Moderate doses of protein, combined with some sugar and keeping fat low should form the basis of your diet. How much protein? Well, maybe you can start with 50g which is what most sick people in the hospital get and seems to be the minimum to ensure organ function without burdening liver or kidneys too much. Try to ingest at least twice as many carbs as the grams of protein in each meal. Then you track temperature and pulse and monitor health signs like fatigue, brain fog, thrist, etc. Increase in any of these probably means increase of ammonia and/or lactate so you need to adjust thing. If is lactate, your muscles would feel sore and limbs would feel heavy and you may start panting from the reduction in CO2. If that is the case, you are probably not processing carbs well so adding things like thiamine and biotin should help. If you get sudden brain fog or your pee smells of ammonia too strongly then either ammonia in blood is too high or you got dehydrated. Adding more carbs and/or sweetened fluids may resolve this. Also, things like zinc or ceylon cinnamon or biotin or thiamine would reduce ammonia in blood. So, now we have two supplements that seem like they would work for both ammonia and lactate - thiamine and biotin. However, if even 50g of protein gives you ammonia symptoms consistently then I'd get some tests done for liver and kidney function as it should not be happening. Another reason for ammonia buildup from small amounts of protein would be extreme hypothyroidism and/or strenuous exercise. Peat said that in one of his articles. But I'd get liver and kidneys checked anyways.
Once you get to a basic diet that does not cause you a stress reaction or symptoms of toxic metabolite buildup you can (if needed) add some metabolic boosting agents like caffeine or thyroid (if needed). Monitor temperature and pulse and if any of these extra substances gives you a stress reaction then either back down or increase nutrients. Overall, the body is very good at regenerating. If you get to a diet that does not harm you (in terms of ratio of protein, carbs, and fat) it takes about 2-3 weeks to get to a much healthier level where you can expand on your success and change nutrient ratios or amounts, add different supplements, etc. Initially I gained more than 30 lbs on the Ray Peat "diet" until I finally figured it out, and for me it was liver function that had to improved with caffeine and vitamin K2 before things got better. That does NOT mean that this is what will work for you since your situation/context is almost certainly different from mine. But that's why you start with something common in all people - smaller meals of basic nutrients that can be controlled and adjusted and once you get to a working version of a diet that does not affect you badly you build up from there. Again, Peat write about many things that are useful IN ISOLATION, but in order for them to be working for you context will have to be taken into account. If your current context (it changes over time like everything else) is such that a supplement or recommendation from Peat stresses you out then it better to work on changing the context instead of forcing that supplement or recommendation on yourself.
Enough ranting, on to controlling serotonin. I can't directly recommend drugs but people have had good responses to small dose cyproheptadine (1mg-4mg daily) and it should be fairly safe UNLESS you have liver disease in which case I'd get that checked first (like I said above). Ondansetron has some great studies behind it in terms of being a very potent anti-depressant in low doses (4mg daily), cognitive enhancer, libido booster, etc. but it seems to have some bad effects on the heart rhythm so if you take it then it should be fairly short-term (less than month). Some of the legal LSD derivatives are (mostly) dopaminergic drugs and include drugs like Bromocriptine, cabergoline, lisuride, etc. They all have very good effects on metabolism and in fact bromocriptine has been approved for the treatment of diabetes type II. See link below.
http://en.wikipedia.org/wiki/Bromocriptine
http://www.ncbi.nlm.nih.gov/pubmed/10937514
I posted studies on cabergoline showing loss of 6g fat in just 2 months, which is unheard of in the medical world unless you take drugs like DNP, which can kill you if you are not careful with the dosage.
viewtopic.php?f=75&t=6287&p=74891
Unfortunately, most LSD-derived drugs (with the notable exception of lisuride) have some nasty side effects including fibrosis or heart and lungs. The side effect comes from the fact that all LSD-derived drugs actually have some (small) serotonergic effects as well. The specific risk of fibrosis comes from agonism at the 5-HT2B "receptor". These should be low risk if you take lower dose and for short term but it's probably not something most people are willing to risk. You can mitigate/prevent the risk by taking a 5-HT2B "receptor" antagonist like cyproheptadine, mianserin, ketanserin, ritanserin, etc. Of these, cypro is the most accessible and safest.
You can also look into newer dopaminergic drugs like pramipexole.
http://en.wikipedia.org/wiki/Pramipexole
Since it is not an LSD-derivative it does not have (relevant) serotonergic properties. As you can see from the Wikipedia page it is also a potent anti-depressant and has effects on fibromyalgia and RLS. The RLS is most likely caused by gut inflammation and/or endotoxin and a number of Peat followers on this forum struggle with the condition. So, since pramipexole cures RLS it probably means it has protective effects on the gut as well. The "bad" things about pramipexole is that is a quite new drug so its full list of side effects is likely not well known. Peat said that it takes about 20 years for a drug to be in circulation to determine what the main side effects are. In addition, it is more expensive and in some people it may cause compulsive behaviors like gambling or OCD. But I am mentioning it as an option to consider for people who cannot tolerate LSD-derivatives or are afraid of the side effects.
Overall, anti-prolactin drugs or substances have the added benefit or reducing also serotonin and estrogen as the 3 cardinal metabolic poisons in Peat world are very tightly correlated and go hand in hand. So reducing one of them tends to lower the other two as well. It just so happens that anti-prolactin drugs seem to have the biggest metabolic benefits with tolerable side effects. Anti-estrogen drugs like aromatase inhibitors (anastrozole, letrozole, exemestane) tend to have unpleasant side effects including depression so most people would not take them. A possible exception is exemestane, which is actually a synthetic version of the hormone DHT and is much safer. Peat has even said that taking DHT topically would be a good idea, so this drug would be a possible alternative to topical DHT. In people it lowers estrogen, increases T and DHT and has anti-depressant activity. The anti-serotonin drugs all have side effects except possibly cyproheptadine at lower doses. So, taking anti-prolactin drugs seems to be the most effective way to improve metabolism via multiple pathways and minimize side effects.
Natural dopaminergic substances include caffeine, magnesium (and most other NMDA "receptor" antagonists), zinc, selenium, vitamin A, etc.
I think this is good as a start. Let me know how it goes and if you need any other help/advice.
Sorry for the big rant but there is a lot of info relevant to metabolism and I did my best to synthesize it.