Depression begins in the gut. More importantly, possible treatment emerges.

5-HTP could help both constipation and depression, but dosage matters.

Photo credit: Hailey Kean on Unsplash
  • New research at Columbia University Irving Medical Center points to a potential treatment for depression.
  • One-third of all sufferers of depression suffer from constipation, strengthening the connection between the mind-gut problem.
  • Slow release 5-HTP was shown to alleviate both constipation and depression in mice.

In 1890, psychologist William James applied the term plasticity to human behavior, implying that humans have the ability to change how we act. Until that point, the science community generally believed fate to be genetic: once born our story was pre-told, a convenient philosophy for those with power and resources, who could simply claim, "it was destined by birth."

Unsurprisingly, James's revelation didn't change many minds. The "born this way" mentality remained the driving narrative. Over three decades later, behaviorist Karl Lashley's research on rhesus monkeys showed that neuronal pathways can indeed change—speculation largely derided by his peers. It would take neuroscientists another four decades, over 70 years after James's initial comments, to come around to the fact that brains are malleable.

Perhaps more importantly, this research also showed no distinction between the murkier realm of mind and the now-measurable domain of neurochemistry. Researchers finally understood that mind and matter are not separate domains but interdependent and necessary pieces of the human puzzle. Though dualism remains our biological inheritance, we can educate ourselves beyond this primal instinct.

Thanks to research by neuroscientist Paul Bach-y-Rita, neuroplasticity became common currency. While fundamental in the field today, behaviorists and psychologists took decades to come around. As psychiatrist Norman Doidge writes in his breakthrough book on the topic, The Brain That Changes Itself,

"The idea that the brain is like a muscle that grows with exercise is not just a metaphor."

We can be astonished that science couldn't recognize a fact as basic as neuroplasticity. Yet ironically, we're wired to not understand how we're wired. Minds might change but they're slow, especially when we're invested in a competing philosophy. This is playing out in the middle of another controversial suggestion that, in a decade's time, will seem like common sense: neurogenesis is possible in the stomach as well.

How Your Gut Influences Your Mental Health: It’s Practically a Second Brain | Dr. Emeran Mayer

That's what a new study, published in the journal, Gastroenterology, claims. A team of researchers from Columbia University Irving Medical Center writes that this new domain of medical knowledge might help to correct gut abnormalities, a growing problem around the world, especially in nations that heavily rely on processed foods. Lead author and pediatric gastroenterologist at Columbia, Kara Margolis says,

"Though it's been known for many years that neurogenesis occurs in certain parts of the brain, the idea that it occurs in the gut nervous system is relatively new."

The study verifies a claim that has been circulating for some time: depression is gut-related. By focusing on the brain it appears that psychiatrists have been missing an essential jigsaw piece for decades. The neurotransmitter, serotonin, is the target of anti-depression medication; SSRIs (selective serotonin reuptake inhibitors) are the most prescribed class of pharmaceuticals for depression and anxiety. Their efficacy has long been debated, especially for long-term usage, which they were not designed for. That's likely because 95 percent of the body's serotonin is produced in the gut, not the brain. Emotions are not a "brain-only" phenomenon, but that's how the medicine has been distributed.

This is why such an emphasis is being placed on our microbiome. As Emeran Mayer writes in The Mind-Gut Connection, serotonin affects not only intestinal functioning, but also sleep, pain sensitivity, mood, appetite, and well-being. He continues,

"Your gut microbes are in a prime position to influence your emotions, by generating and modulating signals the gut sends back to the brain."

In the Columbia study, Margolis and team focused on serotonin's role in constipation in mice. They noticed that shortages in the neurotransmitter lead to a dour mood. By raising serotonin levels in both gut and brain, their depression was alleviated.

William James, 1842 – 1910. American philosopher and psychologist. From The Story of Philosophy, published 1926. (Photo by: Universal History Archive/UIG via Getty Images)

Up to one-third of humans suffering from depression also have chronic constipation, a condition that leads to 2.5 million physician visits and 100,000 hospitalizations every year. Many antidepressant medications lead to constipation, creating a tragic feedback loop. The medicine makes the condition worse. The reduction of gut serotonin inspires enhanced emotional turmoil.

While this observation is clinically useful, the team also discovered a potential cure: slow-release 5-HTP. This precursor to serotonin is widely available as a supplement, though professionals have long warned about overdosing and side effects; for one, it is a popular recovery tool for MDMA users. Nootropic advocates also include 5-HTP in their "optimization" strategies. Yet dosage matters. Just as multivitamins dump a lot of vitamins into your gut without regard for what you might actually be deficient in, getting serotonin levels wrong has consequences.

Margolis notes that supplements approved for sale are immediate-release, too short-acting to be effective in treating depression. Serotonin produced by this method is quickly inactivated. Dialing in the proper dose for a slow-release formula in the treatment of constipation and depression will take a bit of time. More research, including human trials, will be necessary. But the wait could be worth it.

"The idea that we may be able to use slow-release 5-HTP to treat conditions that require the development of new neurons in the gut may open a whole new avenue of treatment."

There is an easier way to tackle this problem now: eat the right foods. Sometimes old folk wisdom is the best medication. That said, the fact that the gut-brain connection is becoming popular science represents an important step forward in battling obesity and depression. We're ready for medicine to take another leap forward.


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Image source: Vaccaro et al, 2020/Harvard Medical School
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  • Surprisingly, the direct cause seems to be a buildup of Reactive Oxygen Species in the gut produced by sleeplessness.
  • When the buildup is neutralized, a normal lifespan is restored.

We don't have to tell you what it feels like when you don't get enough sleep. A night or two of that can be miserable; long-term sleeplessness is out-and-out debilitating. Though we know from personal experience that we need sleep — our cognitive, metabolic, cardiovascular, and immune functioning depend on it — a lack of it does more than just make you feel like you want to die. It can actually kill you, according to study of rats published in 1989. But why?

A new study answers that question, and in an unexpected way. It appears that the sleeplessness/death connection has nothing to do with the brain or nervous system as many have assumed — it happens in your gut. Equally amazing, the study's authors were able to reverse the ill effects with antioxidants.

The study, from researchers at Harvard Medical School (HMS), is published in the journal Cell.

An unexpected culprit

The new research examines the mechanisms at play in sleep-deprived fruit flies and in mice — long-term sleep-deprivation experiments with humans are considered ethically iffy.

What the scientists found is that death from sleep deprivation is always preceded by a buildup of Reactive Oxygen Species (ROS) in the gut. These are not, as their name implies, living organisms. ROS are reactive molecules that are part of the immune system's response to invading microbes, and recent research suggests they're paradoxically key players in normal cell signal transduction and cell cycling as well. However, having an excess of ROS leads to oxidative stress, which is linked to "macromolecular damage and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging." To prevent this, cellular defenses typically maintain a balance between ROS production and removal.

"We took an unbiased approach and searched throughout the body for indicators of damage from sleep deprivation," says senior study author Dragana Rogulja, admitting, "We were surprised to find it was the gut that plays a key role in causing death." The accumulation occurred in both sleep-deprived fruit flies and mice.

"Even more surprising," Rogulja recalls, "we found that premature death could be prevented. Each morning, we would all gather around to look at the flies, with disbelief to be honest. What we saw is that every time we could neutralize ROS in the gut, we could rescue the flies." Fruit flies given any of 11 antioxidant compounds — including melatonin, lipoic acid and NAD — that neutralize ROS buildups remained active and lived a normal length of time in spite of sleep deprivation. (The researchers note that these antioxidants did not extend the lifespans of non-sleep deprived control subjects.)

fly with thought bubble that says "What? I'm awake!"

Image source: Tomasz Klejdysz/Shutterstock/Big Think

The experiments

The study's tests were managed by co-first authors Alexandra Vaccaro and Yosef Kaplan Dor, both research fellows at HMS.

You may wonder how you compel a fruit fly to sleep, or for that matter, how you keep one awake. The researchers ascertained that fruit flies doze off in response to being shaken, and thus were the control subjects induced to snooze in their individual, warmed tubes. Each subject occupied its own 29 °C (84F) tube.

For their sleepless cohort, fruit flies were genetically manipulated to express a heat-sensitive protein in specific neurons. These neurons are known to suppress sleep, and did so — the fruit flies' activity levels, or lack thereof, were tracked using infrared beams.

Starting at Day 10 of sleep deprivation, fruit flies began dying, with all of them dead by Day 20. Control flies lived up to 40 days.

The scientists sought out markers that would indicate cell damage in their sleepless subjects. They saw no difference in brain tissue and elsewhere between the well-rested and sleep-deprived fruit flies, with the exception of one fruit fly.

However, in the guts of sleep-deprived fruit flies was a massive accumulation of ROS, which peaked around Day 10. Says Vaccaro, "We found that sleep-deprived flies were dying at the same pace, every time, and when we looked at markers of cell damage and death, the one tissue that really stood out was the gut." She adds, "I remember when we did the first experiment, you could immediately tell under the microscope that there was a striking difference. That almost never happens in lab research."

The experiments were repeated with mice who were gently kept awake for five days. Again, ROS built up over time in their small and large intestines but nowhere else.

As noted above, the administering of antioxidants alleviated the effect of the ROS buildup. In addition, flies that were modified to overproduce gut antioxidant enzymes were found to be immune to the damaging effects of sleep deprivation.

The research leaves some important questions unanswered. Says Kaplan Dor, "We still don't know why sleep loss causes ROS accumulation in the gut, and why this is lethal." He hypothesizes, "Sleep deprivation could directly affect the gut, but the trigger may also originate in the brain. Similarly, death could be due to damage in the gut or because high levels of ROS have systemic effects, or some combination of these."

The HMS researchers are now investigating the chemical pathways by which sleep-deprivation triggers the ROS buildup, and the means by which the ROS wreak cell havoc.

"We need to understand the biology of how sleep deprivation damages the body so that we can find ways to prevent this harm," says Rogulja.

Referring to the value of this study to humans, she notes,"So many of us are chronically sleep deprived. Even if we know staying up late every night is bad, we still do it. We believe we've identified a central issue that, when eliminated, allows for survival without sleep, at least in fruit flies."

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