Are some people just non-responders to Nootropics?

They are trying to make a joke that all our products are just placebo. However, most people fundamentally misunderstand what placebo even is. They parrot around terms they hear online without actually understanding them. To quickly answer your original question, before I get into placebo, yes; some people are just non-responders to a lot of things. Our old lab director didn't feel anything he took, even alcohol, until he tried Tongkat. That was the only supplement he would feel. I have a friend that feels nothing from IV morphine. Just doesn't affect him at all. They have to use different drugs for him. I have another friend that would fall asleep after doing cocaine. Individual variability in responses to things is woven into the fabric of our society. It's why doctors have to try so many drugs before finding the right one for patients; especially for endpoints like mood or stress. If we all reacted the same way to things, that would make everything much easier. However, that's just not reality. As others have said, it could be your GI tract not absorbing things. That's a thing for some people. It could also just be something central where you don't notice effects as acutely as others. There are changes to the reward pathway that cause a dulling effect in some people. There are a lot of variables at play. Now onto placebo.

There are many different biases that result in statistical anomalies in clinical research. Response bias is a big one in studies that use self-reporting as a metric. That's a tendency for participants in a study to respond incorrectly to questions. It's hard to control for. Many people confuse a positive response bias for the placebo effect, but that's just a fundamental misunderstanding of things. There isn't even a consensus on whether or not a universal placebo response even exists that can't be explained by response bias or one of the others like selection bias, co-intervention bias, attrition bias, outcome reporting bias, and publication bias. Placebo is not taking an active compound, but then consciously convincing yourself of other effects. Placebo is taking an inactive compound and realizing statistically significant effects based on your study design. Unless you are actually blinding yourself and taking sugar pills some days, and active ones on others, you are not experiencing the placebo effect. Nobody is getting a placebo effect with our supplements, because our supplements are not a placebo. Everyone parrots around the term, but what they really mean is response bias. Could some reports from different supplements be, partly or wholly, a result of response bias? Sure, that's a possibility, as it would be in any study. However, we have not sent sugar pills to some customers, and active ones to others. If people want to expand the term "placebo" to encompass any positive response bias towards a compound, then I think we lose all the nuance needed to actually understand what the placebo response really is, and if it even exists in a meaningful way consistently across the board. You also have selection bias big time here on Reddit. People on Reddit like to think they are a normal cross section of the population, but that's NOT the case. There is a massive selection bias happening here on Reddit, both from a demographics standpoint and a psychology standpoint. Anyone acting like random posts on Reddit are an objective sample of reactions is going to have a bad time. Then you also have a LOT of co-intervention bias to deal with. Almost everyone on here is taking something else when they try new things. Very few people washout to baseline before adding a new supplement into their regimen, so the anecdotes you see are colored by that co-intervention bias happening. This is a big one with most nootropics, as many people don't get strong effects from a single compound, but from stacks that all work together. One pretty obvious link is combos with dopaminergic compounds. Activating the dopamine pathway when taking supplements is going to make you feel the effects more acutely. Does that mean you are getting the other benefits? Maybe, maybe not. However, the conscious feeling you get from the dopamine will convince you that you are getting effects. Without proper controls and a universal study design everyone adheres to, you as an observer won't know just how many reports are affected by that co-intervention bias. Then you also have compliance bias to an extent. Not everyone is just using the same dose or combo of things daily for a specific period. Some people jump immediately to large doses. Some people take small doses. Some people take the whole damn bottle in 5 days... All those anecdotes are mixed together on Reddit, seemingly being given the same weight by readers without knowing the context or biases involved. This makes it impossible to make objective determinations using Reddit as a metric.

Placebo effect studies are susceptible to response bias and to other types of biases

Is the Placebo Powerless? — An Analysis of Clinical Trials Comparing Placebo with No Treatment

Back to placebo. People like to feel smart online, so they repeat words they think they understand. However, acting like it is scientific fact that a universal placebo response is a factor in every experience with a compound is not intellectually honest. Yes, some studies have shown placebo to give statistically significant effects in their study design. Other studies have shown that the placebo effect is getting stronger in America, but not in the rest of the world. It's causing real problems for drug development, especially for things like depression, where self reporting is the most common measure of statistical significance. The placebo effect is when those in the control group reach significant effects in the measures chosen for the study design. However, just because the control group had effects doesn't then also mean the active group's effects were due to placebo. I think that is where many people jump the shark. You can have a placebo effect in the control group that's independent of the effect from the active group. A study on fluoxetine used positron emission tomography to see if there were measurable differences between the placebo and actives groups.

The Functional Neuroanatomy of the Placebo Effect

Response to active fluoxetine treatment was also associated with significant regional metabolic changes (scan 3 minus baseline metabolism: beta-2=3.44, df=1972, p<0.0006). The pattern of metabolic change closely matched that seen with response to placebo (Table 2, right). Drug responders, however, showed additional changes in metabolism in subcortical and limbic regions (Figure 1, bottom). Specifically, fluoxetine response was associated with unique increases in brainstem metabolism and metabolic decreases in the striatum, hippocampus, and anterior insula. There were no regional changes that were unique to placebo responders at 6 weeks.

The interesting thing about this study was that they empirically measured changes in the brain, not just relied on self-reporting measures. They found common changes in the brain in the placebo and fluoxetine group. However, there were additional changes and stronger effects in the fluoxetine group. They also showed that there were drug non-responers AND placebo non-responders. This is what everyone has to realize with research. They are looking for STATISTICAL significance. That doesn't mean everyone reacted the same, both to the active and placebo. Sometimes statistical anomalies are just that, statistical. There is always variability between patients/participants. If we have drug responders, drug non-responders, placebo responders, and placebo non-responders in the same study, how can anyone deny the reality that our bodies and brains are incredibly complex and variable?!?

Placebo responders and nonresponders: what’s new?

Some researchers have even tried to select for placebo non-responders to see if they could overcome the placebo effect. The placebo effect is also most seen in pain and depression research, which is largely self-reported.

Enrichment designs using placebo nonresponders

So again, the idea that we are all different, and will respond differently to many things is not just some abstract opinion on Reddit. It's a measurable fact of life. Not everyone is going to react the same to things. Every supplement will have similarities in the way people respond. Some people will love it. Some people will hate it. Some won't feel anything from it. Some will get strong effects. Some will get weird side effects that we might not fully understand. It can be frustrating for the people that have not found something that works for them yet, but that's just the fact of life. It sometimes takes a lot of trial and error to find what will work best for you.