Creatine’s Unexpected Link to Depression

There was an antiquated view of depression that revolved around a simple imbalance of molecules called neurotransmitters exchanged between brain cells called neurons. As more research is released, we've had to continuously update our view of the complexity of depression. Now, there's a new high-impact study that implicates the popular molecule creatine, yes, the same one people supplement with, in depression, and it seems to work through the gut. What's especially fascinating is that a lot of previous research paints a different story. So, what's the deal here? Well, to find out, I analyzed 17 studies in total to make sense of this new study, and it actually may fit together like a puzzle piece, assuming

that you have the right perspective. Let's start here. The newest study that I just showed you compared people without major depressive disorder and those that were diagnosed. Then, they compared their blood, poop, and cerebrospinal fluid, the liquid that's around the brain, and tested the concentration of creatine found in each compartment. They did a lot more than that, but that's not what we'll focus on here. And, as we see here, the higher the violin data, which are these blobs, the more creatine is present. The blue are those with major depression, and the red are the controls without. In blood and cerebrospinal fluid, there's reduced creatine concentration in the depressed individuals, and yet, in their feces, the poop, they were increased in level. So, what does that tell us? Well, it tells us that a molecule that is heavily implicated in metabolic health, creatine, is not as abundant in the key regions of the body. Keep in mind, creatine allows your cells to have bursts of activity that are not possible with other sources of energy, like glucose or fat. Why is that? Why do we see such differences between the groups and the compartments? I mentioned your gut at the beginning, and that's where we cross from poop to blood, right? I mean, the barrier between the two is there. But, importantly, there are billions of microbes found in the gut called the microbiome. So, what if we were to take the microbes of the people with depression and the microbes from the people without depression, and we implant them into mice? What happens to their blood creatine? There is a reduced blood creatine in the mice exposed to the depressed patients' microbiome. This all tells us that our microbiome is directly implicated in affecting blood creatine concentrations. It also tells us that people diagnosed with depression have a microbiome that reduces body creatine stores. When investigated more closely, there are also significant differences in the number of specific bacteria between non-depressed diagnosed and diagnosed. And those differences are then implicated in reduced creatine absorption at the intestinal level. Ultimately, at the end of this, when the dust settles, this inhibition of creatine uptake at the gut leads to reduced delivery of creatine to the brain, which has consequences that are apparent in people with major

depression. Okay. That's a lot going on, and there's a lot of human studies that have looked at creatine supplementation and the impact that it has on depression directly. Unfortunately, the literature is incredibly mixed. I said I went over 17 studies, and we have nine studies that indicate an effective creatine and seven studies that show no effect. And then there's one meta-analysis of 11 randomized control trials that indicates a benefit of creatine supplementation against depression shown here. Now, there's all of these studies listed on the left and the individual studies data are on the right side, but we can focus on the blue overall effect diamond at the bottom. Since it leans left, there's an identified effect. However, even the researchers point out that while statistically there's an effect, clinically they'd consider it too small to make any real difference. So, talk about a hodgepodge of results. I'm not going to bore you with every specific of every study. I'll cut straight through to the through line distinguishing these studies. Almost every study that failed to show a benefit of creatine was either a tiny study like this one including 13 total participants in very specialized populations like people recovering from stroke. Or even if they were big studies done over long periods of time like this one that included I don't know over a thousand participants and aimed to measure creatine's effects across years, this study also was exclusive to people with Parkinson's disease and the primary outcome was not depression. In fact, while all these studies did measure depression, which is why I looked at them, only a single study was in people with clinically diagnosed depression of these seven dissenting studies. On the flip side, every study that showed a reduction in depression from creatine was in people with clinically diagnosed depression. I think that's a critical foundation to the creatine research, not just the outcome, but the population. Though, that's probably a dull statement to you. The next feature is being treated for depression. Most had treatment-resistant depression and were taking medications for depression. I don't think I found any studies that showed creatine was effective by itself. We'll return to that point because there's a potentially good reason why not. The bottom line is that there is a through line across eight studies that creatine reduces depression severity in people dealing with treatment-resistant, clinically diagnosed depression when also treated with depression medication. I don't want you thinking that all these studies were big, well-controlled studies though. Some were small, had no controls, and had other flaws. The reason I'm still positioning it that way the way that I am is because the largest, most well-controlled studies still follow this through line. Now, this may also explain why the meta-analysis found an effect, but the effect is tiny, especially as they included that huge Parkinson's study that I mentioned earlier, which influenced the analysis in the no-effect direction. Now, plenty more I could parse out there, but let's leave it with that main point. But, there's a massive

variable missing here because while these clinical studies did look at creatine supplementation and depression, they don't take into consideration these new data about the changes in microbiome from this new study. And of course, it's impossible for them to have considered it as the study just released. Fortunately, this primary study did a small clinical trial of its own. They took those clinically diagnosed with depression, that's the critical foundation that we discussed, then measured the depression using the HAM-D score, a better version of the Turkey B score, then randomly assigned them to consume placebo or creatine plus one of the bacteria implicated in affecting blood creatine levels, and then measured depression score again. Before I get into those details of this more specialized trial, if you're interested in learning more about the interaction between these gut microbiome bacteria and the brain creatine or the relationship to mitochondria or even the relationship between creatine and antidepressant drugs and a molecule that may recover creatine in the body for people dealing with depression based on early mechanistic data and more then check out my full analysis. It's included as a Physionic Insider, my premium research platform and community. You also get all of this in article format, podcast format and much more. Some are listed right here. And keep in mind that's true for all of my research reviews released over the last year and a half. Anyway, if you want access to all my work, check out the Insiders. The link to join is in the description box. I'll catch you over there. Here are the results. The higher the bars, the more change in the positive direction. The right blue bar is those taking creatine and the bacteria. Clearly, there's an improvement and the effect size speaking to that meta-analysis critique was sizable. The HAM-D test is a 17-point measure. So, we're seeing about a 9-point improvement. Granted, a good chunk is placebo as indicated by the red condition there, but there's still a meaningful reduction in depression which is pretty incredible. Now, do I put my scientist hat back on or would you prefer that I leave it there all excited and in a frenzy as we go away thinking that creatine will cure us of depression? I'll opt for the former. It still wasn't a huge study, but it was only a month in duration. In addition, I would have liked to see a third condition of separating creatine from the bacterium itself because truly, we don't have clinical evidence indicating that it's one or the other or the combination specifically. That means that while I'd like to see more robust data in people with clinical depression, the evidence leans in the direction of creatine being effective for those people and likely ineffective for people without clinically diagnosed depression as expected. Now, the second layer to this where we only have this one new study is if the microbiome might play a major role in influencing if creatine is effective or not. So far, early evidence leans yes, but again, more data is going to be needed to be certain. Plus, most studies used 5 g of creatine and while that seems to have provided some benefit, there's an argument to be made for using greater doses closer to 20 g based on some studies looking at brain creatine levels like the ones that I've discussed right here. I hope this fascinated you as much as it did me. Plus, I got to speak about creatine some more, which if you know me, that's a fun time for me.