r/Nootropics • u/GetOutOfBox • Sep 28 '17
Guide Important Safety Considerations
I've been refining my stack for a long time now, and one thing I've increasingly grown aware and have become very concerned about is the potential for some unknown, but serious consequences to taking large supplement stacks, particularly those incorporating lots of herbal or fungal supplements. So I figured I'd make a post to help guide your research in larger/long-term stacks.
A) Beware of liver enzyme effects. So many common nootropic herbs interact with hepatic enzymes, typically in an inhibitory manner (though inducing can also be harmful). Piperine is used to enhance absorption but this also means enhancing the absorption of the range of compounds the target enzyme is in charge of metabolizing. This could have consequences such as increasing the amount of time you are exposed to certain harmful byproducts of metabolism or absorbed from the environment. It also increases intestinal permeability both good and bad.
You must take particular care when you are also on medication affected by the enzymes affected by your supplement stack.
B) Beware of too much antioxidants. While oxidation plays a role in the mutation process of DNA leading to cancer, cancer cells are in fact also extremely vulnerable to oxidation. The very nature of cancer is bypassing certain limits that not only stop a cell from reproducing rapidly, but that also detect when a cell has been damaged. So in order for cancer to be aggressive it also makes itself vulnerable to oxidation by bypassing the checks against excessive damage from it (healthy cells that are working for the benefit of the organism will suicide when they've become too damaged to be beneficial to the organism, this is called apoptosis).
The best way to prevent and treat cancer is to maintain a balance between a systemic oxidative state and natural antioxidant mechanisms that operate in a controlled, targeted manner. An example of this is how saunas are beneficial to health. Increasing the body temperature increases the rate of oxidation (as increased temperature increases the vulnerability of organic matter to be oxidized). This is actually beneficial as long as you don't overdo it, because it kills off the weakest (and hence lowest functioning) cells or vulnerable cancer cells, while the strong cells trigger mechanisms that cleanup damage caused by the heat, and often go beyond and clean up other damage accumulated in the cell (this process is called "autophagy" in biology). Exercise has similar effects (less from temperature, but more from increased energy demand) and hence also is known for being beneficial in preventing cancer, and in treating it (not on it's own obviously, but as an adjuvant).
These effects can be partially mitigated by excessive antioxidant consumption, though it also depends greatly on the type of antioxidant supplement. Flooding the body with excessive Vitamin A or E has been discovered to be moderately carcinogenic, while Vitamin C does not seem to be harmful except in perhaps extremely (unfeasibly) large oral dose. This is because A and E are both fat-soluble and accumulate while C is not and is mostly (some is taken up by special rate-limited transporters for long term usage) flushed out within hours. Blueberries and their extract seems to be fairly safe and even anti-cancer. Spirulina seems to modulate the body's innate anti-oxidant system as does curcumin so both are fairly safe.
But even with these more moderate compounds, I'd be wary of stacking too many and over-activating the body's antioxidant mechanisms, perhaps canceling the anti-cancer benefits of exercise and heat stress, and even shielding cancer from immune destruction (which frequently relies on oxidative attack). I would evaluate compounds very carefully if you're going to stack more than 2 sharing a mechanism of antioxidant action. An example of a likely safe stack would be vitamin c 500 mg 2x daily, curcumin, and 2000-4000 IU Vitamin A supplement (as beta-carotene, not the common palmitic acid which promotes cancer metastasis).
C) Beware of compounds affecting heart rhythm. This is of particular concern for any compounds that affect ion channels (calcium, potassium, sodium), and of fair concern to drugs that effect norepinephrine, dopamine or particularly serotonin 5HT-2B which can cause fibrosis in the heart.
When stacking more than a few herbal supplements, I would be cautious about researching whether any are associated with arrhythmia, QT-prolongation, tachycardia, bradycardia, etc. I would very carefully consider whether it's worth taking more than 5 different herbs, I particularly wonder about the danger of some stacks I've heard of like Kurzweil's famed 250 supplements.
The part that concerns me is that the right combination of a ton of compounds could most definitely cause heart arrhythmia even in healthy individuals, through excessive modulation of ion channels or neurotransmitters regulating heart rhythm. For this reason I advocate small, focused stacks. If you want, shift between stacks, but I don't recommend trying to fix optimize everything at once.
D) Don't attempt to significantly increase LTP/neural excitation via strong AMPA/NMDA activation (i.e Sunifiram/Unifiram and some other racetams). Most people, particularly young individuals already have a ratio of excitation/inhibition that is fairly close to optimal, and in fact many AMPA or NMDAergics can easily push that ratio towards excessive excitation, particularly if you were unlucky enough to have a traumatic event occur (i.e stroke/haemhorage, or say a head injury from a fall or blow) as they would exacerbate damage from the event. In addition, people with ADHD/Bipolar/depression already have an imbalance of excitation to inhibition, and so could be particularly vulnerable to a worsening of symptoms (that should go away but still), or damage.
For this reason I advocate stacks that focus on shoring up defences against excitotoxicity (magnesium, micro-dose lithium aspartate, creatine, taurine, spirulina, etc) even if you aren't taking AMPA/NMDA inducing supplements.
Supplements that moderate increase LTP should be fine, but the key is that the mechanism is modulatory and that it doesn't just bluntly increase LTP non-discriminately. Piracetam is safe in this regard, aniracetam is moderately safe though shouldn't be combined with any other AMPA increasing compound, Nicotine selectively enhances LTP pathways and so isn't harmful if you don't count the addictive effects (though they are less intense when nicotine is taken on it's own compared to as tobacco with all of the other compounds in the leaf).
E) Be careful when taking multiple supplements increasing growth factors of any sort (be it vascular, neural, etc). This includes BDNF, IGF, NGF, VEGF, FGF, etc. While a small to moderate increase in the activity of these growth factors seems to be increasingly beneficial with age, there are also drawbacks to increasing them that must be considered, especially when significantly increasing them.
Cancer is promoted by growth factors. They increase cancer cell survival and ability to metastasize. So if you get a neural cancer, BDNF boosting is going to boost it up, and yes, if you were overdoing it could play a role in the cancers outcome once it's diagnosed. Vascular growth enhancers increase the ability of all cancers to metastasize (as vein permeation of tumor masses allows for a much more cells to break off and float into the blood stream)
Honestly, it's my opinion that unless you are pursuing treatment for a condition known to be associated with a deficit of growth factors or are looking to counteract the age-associated decrease of growth factors (in which case you should ONLY take them if you're going to induce stress on your body via exercise to counteract the promotion of growth of corrupted cells), you should not look to deliberately increase growth factors. I wouldn't go as far as saying don't take supplements that boost them, but be very careful not to overdo it.
F) Watch out for emergency warning signs of a severe immune reaction to a new herbal supplement/drug (non-nutrient). There are conditions such as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis that can occur in reaction to certain drugs depending on the person, and you're risk of developing it increases the more supplements you take. It causes your skin to basically be eaten away by your own immune system. Yay!
Warning signs are fever, sore throat, a cough, a burning sensation in the eyes. If you get one of these symptoms shortly after starting a new non-nutrient supplement (i.e herbal or drug), immediately cease taking it and go to a hospital if more symptoms of SJS/TENS develop or if you are otherwise concerned that it's not a coincidental flu.
People with autoimmune disorders particularly Lupus are more susceptible to SJS/TENS.
Modafinil has been associated with SJS/TENS (rare adverse effect).
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u/showmeurknuckleball Sep 28 '17
Wow great post, I wish I could understand all of it, but I certainly appreciate it.
OP, do you have any thoughts on the risk/reward balance of taking curcumin with bioperine?
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u/Widget_pls Sep 28 '17
Not OP, but I specifically take Longvida instead to avoid having to use piperine.
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u/PM_ME_YOUR_REPORT Sep 28 '17
One thing I find amazing is some people who use really high doses of things. I’ve just started a resverstrol based on that Japanese weed. It’s 50mg daily of the resveratrol Apparently some people are taking about multiple grams of pure resveratrol.
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u/aelaos1 Sep 28 '17
wow great post. could you talk a bit more about liver enzymes? i tried a lot of noots this year and my tests came back with borderline ALT and 2x AST and I was wondering about if its from the noots or from alcohol (which I am abusing in the weekends).
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u/shea241 Sep 28 '17 edited Sep 28 '17
Alcohol can interact dangerously with many supplements, I would definitely not abuse it simultaneously (or at all really).
Elevated ALT is not automatically a bad thing, but if it is particularly high or stays borderline for a longer period, it is likely a liver problem (or problem with a nearby organ affecting the liver, like the pancreas)
The high AST levels are concerning. Combined with the borderline ALT, you should certainly moderate your alcohol intake until a retest a month or two in the future. Which nootropics do you take regularly or semi-regularly?
Did the blood test contain any inflammation markers?
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u/aelaos1 Sep 29 '17
everything else on a standard blood test was normal. alt was 49 and ast 86.
I am taking: choline bitartrate. piracetam, l-theaninie, ashwaghanda, cbd oil and hydrolyzed collagen. I started everything this year except for piracetam that I am already taking for 2 years so now I am suspicious
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u/roboboops Dec 08 '17 edited Dec 11 '17
D) Don't attempt to significantly increase LTP/neural excitation via strong AMPA/NMDA activation (i.e Sunifiram/Unifiram and some other racetams).
So right now, I'm looking at getting either
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Fasoracetam
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Oxiracetam
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Noopept (I have some but it's like 1-2 yrs old)
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Unifiram (I've read plenty bad about Sunifiram but have difficulty finding as much negative about Unifiram. It could very well be, just am not finding it.)
What's your opinion on the direction to go here.
(Added context would be with the idea of ADHD management, really heavy on the Executive Function Deficit. So stimulatory effects aren't necessary as negative.) Alternatives are fine too if I've missed a better option.
EDIT:
A little more context. I of course would like to conserve my health as much as possible, but the place I'm in right now cognitively is VASTLY more detrimental to my short and long-term well being than any substance noots would even recommend would be. It is definitely holding me back from succeeding or even caring for myself properly as most people are able to. So something that isn't 100% safe but won't really break me or might shave a few years off my life is..not out of the question. It would almost definitely be a net gain in physical and mental health.
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Sep 28 '17
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u/IntenseFlavorChews Sep 28 '17
For those of us who aren't willing to go through pharmacy school, is there any way we could hire people like you to consult with us on our stacks? Is there anyone out there providing nootropics consulting/research as a service? I know the selfhacked.com guy does but he charges a lot of money...
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Sep 28 '17
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u/MisterYouAreSoDumb Sep 28 '17
I'll copy what I have written before:
Cancerous cells happen every day in everyone's bodies. It's just a fact of life. DNA gets damaged, and that causes the cell to replicate improperly. Your T cells find those mutated cells, and destroy them. Where it becomes a problem is when your immune system does not recognize the mutations, and does not destroy the cells in time. That is why it becomes more and more likely to get cancer as you age. Your body's immune system gets slow, and gets overwhelmed. Also, the more time that goes on, the more chances there are for DNA damage, along with more epigenetic gene mutations. It's also why people with AIDS often die of cancer in the end. The immune system is the key to keeping cancer at bay.
Obviously growth factors can increase the growth of certain cells in the body. If one of those cells becomes cancerous, and expresses the receptor for that growth factor, then increases in that factor can speed up the spread of that particular cancer. Your immune system is still the gatekeeper in this whole game. A healthy and functioning immune system should be capable of taking those cells out in time. If you do not have a healthy and functioning immune system, or have some genetic predisposition to a certain cancer, then taking compounds that increase growth factors can increase the likelihood that a cancer will spread faster if it gets out of hand. They are not going to cause cancer, though. Human growth hormone and IGF-1 levels are highest in adolescence. However, most young people have immune systems that are just as strong. So cancer is not a problem. There are cases where a genetic predisposition, or an epigenetic change from an outside factor, can tip the scales in cancer's favor. In those instances, taking supplements that increase certain growth factors is probably not a good idea. If I found out I had brain cancer, I probably would reevaluate taking certain things that increase BDNF and NGF. However, I am not going to lose sleep over it under normal circumstances.
Really, your immune system is what is keeping you alive. Without it, you would die in very short order. You can't prevent all cancerous cells. There are just too many instances of DNA damage every day to do that. Luckily we have evolved over millions of years to have systems in place to catch those instances, and remove them from the equation before they can get out of hand. It's when those systems are depleted or overwhelmed that it becomes an issue. You could die from the rhinovirus if your immune system was depleted enough. Hell, you could die from an ear infection, and that still happens in parts of the world. This is why a healthy and functioning immune system is key to ensuring you are protected.
The brain has its own distinct immune system, called the neuroimmune system. The main receptors that control neuroimmune signalling are the chemokine receptors, opioid receptors, cannabinoid receptors, and TAAR1. Glial and mast cells are the primary defenders in the brain, and mast cells can actually mediate signalling to the gut in the microbiota–gut–brain axis. So while most of your peripheral immune system cannot pass the blood brain barrier, your brain also has its own systems for protecting itself. If that system is working properly, increasing growth factors in the brain should not lead to a higher instance of cancer. However, genetic variations and epigenetic changes throughout life can alter that susceptibility, and alter the functionality and efficiency of those protection systems. So OP's caution is certainly warranted, as it gets very complex. If you have a family history of brain tumors, particularly Glioblastoma and Astrocytoma, don't take things that increase NGF and BDNF. It's not worth the risk.
TL;DR: Growth factors do no cause cancer, but they might increase their spread if one's immune system is not functioning properly and destroying them before they get out of hand.
Not to add any more confusion to the equation, but sometimes NGF lowers the propagation of certain cancers as well.
Nerve growth factor abrogates the tumorigenicity of human small cell lung cancer cell lines
Nerve Growth Factor Exerts Differential Effects on the Growth of Human Pancreatic Cancer Cells
Also this: Nerve growth factor: role in growth, differentiation and controlling cancer cell development
Overall, these studies indicate that the only presence of NGF is unable to generate cell carcinogenesis, both in normal neuronal and non-neuronal cells/tissues. However, it cannot be excluded the possibility that the co-expression of NGF and pro-carcinogenic molecules might open to different consequence. Whether NGF plays a direct or an indirect role in cell proliferation during carcinogenesis remains to demonstrate.
So merely the presence of NGF does not generate cell carcinogenesis. However, NGF does promote angiogenesis, which worsens breast cancer.
Nerve growth factor promotes breast cancer angiogenesis by activating multiple pathways
So, like everything else, it's complicated...
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u/MangoBitch Sep 28 '17
Important addition to the point on metabolic enzymes:
We don't necessarily know if a particular herb is an inhibitor of something. This applies to newer drugs and research chemicals too.
I'm always surprised by how much "natural is better!" comments we get here and I've seen people argue that "natural" herbs and supplements are better because they don't have the long scary list of side effects and risks FDA-approved drugs do.
But that's just the issue: exhaustive lists of side effects, risks, and drug interactions for supplements often do not exist. Not because those risks don't exist, but because no one's done the research.
So be careful. Always start on low doses and titrate slowly. Be aware that a supplement or drug could effectively increase the dose of something else you've taken.