New research illuminates how the human brain creates its own psychedelic drugs

A new study challenges serotonin's role in depression, while partly explaining why our bodies make drugs like DMT

By Troy Farah

Science & Health Editor

Published February 20, 2023 2:00PM (EST)

Mushrooms And Mental Health (Getty Images/wildpixel)
Mushrooms And Mental Health (Getty Images/wildpixel)

We are rutted in a deepening mental health crisis that is shortening our lifespans and undercutting the economy. The World Health Organization estimates that incidence of conditions such as depression and anxiety rose by more than 25 percent in the first year of the COVID pandemic, adding to the nearly one billion people who were already living with a mental disorder. Meanwhile, more than 800,000 people worldwide die from suicide annually.

"Everyone's life touches someone with a mental health condition," Tedros Adhanom Ghebreyesus, the director-general of the World Health Organization, said last summer. "The inextricable links between mental health and public health, human rights and socioeconomic development mean that transforming policy and practice in mental health can deliver real, substantive benefits for individuals, communities and countries everywhere."

One of the principal ways mental health disorders are thought to manifest is through severed connections between neurons — the winding, spindly cells in our brain and throughout our body essential for interpreting info from the external environment. Our brains are essentially fat, watery bags of neurons that are tangled together like a dense thicket of thorny weeds.

Depression and other mental health problems can act like weed killer, shriveling these connections and making it harder to function cognitively. This is known as the neurotrophic theory of depression and psychedelic drugs like ketamine (which is also a dissociative anesthetic) seem to reverse this relationship.

In contrast, certain antidepressant drugs like fluoxetine (Prozac) seem to work by increasing serotonin levels, an important neurotransmitter that the brain uses to send signals between neurons. These drugs are called selective serotonin reuptake inhibitors (SSRIs) because they stop neurons from recycling the neurotransmitter. With more serotonin available, the brain can communicate better and depression alleviates. At least, in theory.

Unfortunately, SSRIs and other antidepressants can come with significant drawbacks. They don't work for everyone, can take weeks to months to kick in and sometimes have side effects like sexual dysfunction and weight gain. To address the growing degree of mental health deficits, we need more and better tools to heal the brain.

Many experts believe psychedelic drugs could play a substantial role in addressing this problem. They seem to act like Miracle Grow for neurons, helping them flourish like a dense forest. Once relegated to the fringes of science thanks to their notorious hallucinatory effects, psychedelics like LSD, psilocybin and ayahuasca are gaining more mainstream recognition for their ability to alleviate mental suffering and help people self-actualize. A handful of states have repealed laws banning these substances (but are still highly illegal most places) while scientific research on psychedelics has skyrocketed in the past decade.

Many patients with depression seem to experience an atrophy of the prefrontal cortex, an area of the brain associated with regulating emotional responses.

The more we study psychedelics and related drugs, the more we learn about how the brain functions and how to better repair it when it goes haywire. A new study published in the journal Science illuminates the relationship between changes in the brain and serotonin using psychedelics in mice to show how different cells react. These reactions are what seems to create changes in the brain that improve mental health.

Serotonin has been implicated in many prominent theories of depression, but this is generally an oversimplification. This research emphasizes that it's not just the molecule that matters, but where the receptor is located. It also suggests that the body could be producing its own natural psychedelic compounds, though what those might be or what they might be doing is somewhat of a mystery.

"The theory a long time ago has been that if you increase synaptic levels of serotonin, then you could produce antidepressant effects," Dr. David Olson, the study's lead author, told Salon. "Where this paper comes in, is maybe explaining one of the reasons why that is. And that is the key receptor for the neuroplasticity-promoting effects of psychedelics is on the inside of the cell and is inaccessible to serotonin."

Olson is the newly appointed director of the Institute for Psychedelics and Neurotherapeutics at University of California Davis and a co-founder of Delix Therapeutics, Inc., a psychedelic biotech company. In this experiment, Olson and colleagues experimented with chemically tweaking psychedelic drugs to see how easily they can cross cell membranes in the brains of mice. Serotonin is not able to cross this membrane, but certain psychedelics can. They found that the drugs that better crossed this membrane, such as DMT, was correlated with more neuron growth.

SSRIs can help regrow neuronal connections just like psychedelics, only the effect seems to be slower and less dramatic.

Therefore, serotonin may not play as big a role in treating depression as once thought. This is in line with research published last summer in the journal Molecular Psychiatry that systematically reviewed 17 studies and found "no consistent evidence of there being an association between serotonin and depression."

In other words, serotonin's influence on depression, also known as the monoamine model of depression, seems to be wrong or at least incomplete. Unfortunately, what many people on social media took away from this study was that SSRI drugs are worthless and don't work. That is far from the case. Many people greatly benefit from these drugs. The Molecular Psychiatry study simply indicates SSRIs work via a different mechanism, which is still unknown. They can help regrow neuronal connections just like psychedelics, only the effect seems to be slower and less dramatic.

Olson explains that many patients with depression seem to experience an atrophy of the prefrontal cortex, an area of the brain associated with a wide range of cognitive functions, including regulating emotional responses, which is related to mental health.

In a depressed patient, "The neurons retract their dendrites, they cull their synapses, they have ineffective communication with their neighbors," Olson says. "And what the SSRIs tended to do is to regrow these neurons. But here was the rub: they did so on a timescale that correlated with their clinical efficacy, not with their ability to promote serotonin increases in the synaptic cleft."

It is rather bizarre that our bodies make trace amounts of a chemical that is also created by toads to serve as a psychedelic venom.

In other words, if serotonin really was what was helping alleviate mental health problems, then SSRIs would presumably work much more quickly. Again, they can take weeks to start working. In contrast, psychedelics can promote this kind of regrowth in as little as 24 hours, often less.

But Olson's recent research gives us a better idea of how this happens and it seems to be related to the location of the serotonin receptor, on the inside on the cell, rather than the outside.

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This leads into the intriguing study of how and why the human body produces its own psychedelic compounds. Our bodies already produce its own opioids (called endorphins) and endogenous cannabinoids, which are like the drugs in marijuana. In fact, pretty much the only reason drugs have a psychoactive effect on us at all is because they closely resemble chemicals our body already produces. And some research indicates that humans naturally produce the psychedelics DMT and bufotenine, as well as mebufotenin (5-MeO-DMT), a powerful psychedelic also found in toad venom. However, the amounts of these drugs probably aren't substantial enough to "trip."

If you think about it, it is rather bizarre that our bodies make trace amounts of a chemical that is also created by toads to serve as a psychedelic venom. But as the Science study points out, "they are rapidly degraded in vivo [in a living organism], which makes their detection by classic analytical methods quite challenging," Olson and his colleagues wrote, meaning they can be hard to find, let alone figure out their function. They concluded, "The possibility that endogenous psychedelics play a role in health or disease should therefore be thoroughly investigated."

The fact that our bodies makes psychedelic compounds actually isn't so remarkable — many animals and plants produce DMT or similar compounds — but researchers still aren't sure what DMT is doing there in humans.

"The big question is, where are they produced? When are they produced? And what quantities are they produced?" Olson says. "And that is completely unanswered. And so a lot more work needs to be done, but it's quite possible that they are playing some kind of role in just normal physiology."

Most psychedelic drugs like LSD, DMT and psilocybin are structurally similar to serotonin, so they can act on serotonin receptors, but in a slightly different way. You can think of it like clumsily-made lockpicks that still work in a lock designed for a specific key. But even the slight differences can have profound effects, specifically, altered perception of time and space and intensified colors and sounds. This is why these drugs can trigger hallucinations.

Such hallucinatory experiences can be pleasant or uncomfortable, depending on the situation. Of course, psychedelics are not a panacea and not everyone will benefit from them. In fact, not everyone can or should take them. People with heart problems or conditions like schizophrenia are generally discouraged from taking psychedelics. And some folks that take them still don't necessarily experience miraculous recovery.

That's why Olson's lab is working on non-hallucinogenic compounds that are similar to psychedelic drugs, called psychoplastogens. Olson's lab has produced analogs of drugs like DMT and ibogaine that are seemingly devoid of the psychedelic aspect but still promote those changes in the brain, which could help someone who couldn't handle a mushroom trip.

Olson says his lab is intending to test these substances for the first time in humans later this year in May. Despite lacking those trippy, introspective effects, psychoplastogens are not intended to replace SSRIs or psychedelics, but instead could give us an additional tool to fight mental health problems.

Of course, a chemical solution to mental health is only part of the equation. Let's not ignore the fact that our planet is crumbling thanks to climate change and pandemics, while income inequality is rampant throughout a stumbling economy. There is considerable research that depression and anxiety are just as much linked to society and the environment as they are to chemicals in the brain.

But it's worth researching if psychedelics, SSRIs or related chemicals can help people and how exactly they function in the brain. Given the scale of our mental health crisis, even relieving a little mental suffering will go a long way.

By Troy Farah

Troy Farah is a science and public health journalist whose reporting has appeared in Scientific American, STAT News, Undark, VICE, and others. He co-hosts the drug policy and science podcast Narcotica. His website is and can be found on Twitter at @filth_filler

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5-meo-dmt Brain Dmt Health Mental Health Neuroscience Psilocybin Psychedelics Science Serotonin