Scientists Now Know Why Psychedelics Conquer Depression Even Without a High

Everyone is raving about hallucinogens as the future of antidepressants.

LSD (better known as acid), psilocybin (the active ingredient in magic mushrooms), and the “spirit molecule” DMT are all being tested in clinical trials as fast-acting antidepressants.

And I mean fast: when carefully administered by a doctor, they can uplift mood in just one session, with the results lasting for months. Meanwhile, traditional antidepressants such as Prozac often take weeks to see any improvement—if they work at all.

But tripping all day is hardly a practical solution. Unlike Prozac, hallucinogens need to be carefully administered in a doctor’s office, under supervision, and in a comfortable setting for best therapeutic results. It’s a tough sale for busy individuals.

Then there’s the elephant in the room: psychedelics are still classified as Schedule I drugs at the federal level, meaning that similar to heroin, their possession and consumption is illegal.

What if we could strip the trip out of psychedelics, but leave their mood-boosting magic?

This week, a new study in Nature Neuroscience suggests it’s possible. Led by Dr. Eero Castrén, a long-time champion of psychedelic research for mental health, the Finnish team dug deep into the molecular machinery that either lifts mood or gives you a trippy head rush.

The results came as a surprise: similar to traditional antidepressants, psychedelics spurred new growth in both baby and mature neurons. But the mind-bending substances were 1,000 times more efficient than Prozac at grabbing onto a key molecular hub, TrkB. With just a single dose, the drugs elevated mood in mice under chronic stress and reduced a previously-established fear. However, when genetically stripped of a critical protein site, LSD lost its magic.

It’s still early days for re-configuring psychedelics as antidepressants. But the results “open an avenue for structure-based design” that can skirt unwanted hallucinations while developing fast and long-lasting antidepressants, the team said.

Meet the Players

Think of neurons as a fast-growing basil plant. It starts as a tiny sprout. With nutrition it blooms into a bushy wonder. Pruning the plant along the way helps its health and survival.

In neurons the main nutrient is BDNF, or brain-derived neurotrophic factor. It’s the all-star of rejuvenating the brain. In the hippocampus—a brain region critical for memory and mood— it helps nurture new neurons through life, cradling neural stem cell “seeds” into maturity. The protein is also essential for rewiring neural networks by pruning connections—a process called neuroplasticity. It’s a fundamental process in the brain that allows us to learn, adapt, and reason in an ever-changing world. Neuroplasticity is especially important for battling depression, as the condition often “locks” people into negative mindsets.

BDNF doesn’t act alone. It floats outside of neurons. Grabbing onto it is TrkB, a protein that usually lies low inside neurons until it’s time to rise to the top—literally. Once on the surface of neurons, it captures floating BDNF. The union then triggers a cascade of molecules that help the neuron branch and grow. Similar to roots on a growing basil plant, TrkB is key to letting brain cells absorb nutrients to promote growth.

Most conventional antidepressants, such as Celexa, Lexapro, Zoloft, and Prozac trigger this nurturing pathway. These medications, dubbed SSRIs (selective serotonin reuptake inhibitors) enhance a chemical called serotonin by blocking its recycling to increase levels in the brain and boost mood.

The downside? Serotonin is also the trigger for hallucinations from psychedelics.

An Atomic Dissection

The new study focused on these two pathways: the nurturing TrkB and the classic serotonin.

Using a myriad of experiments, the team first confirmed that psychedelics grab onto TrkB in cells in petri dishes. Think of TrkB as floating pieces of paper—two need to be united to activate the growth-supporting BDNF. Surprisingly, compared to traditional antidepressants, LSD was able to glue together the paper pieces and stabilize TrkB so that it better captured BDNF. One protein site was critical. When mutated, LSD could no longer organize the TrkB duo.

So what?

A further deep dive found that LSD activated the molecular cascade to increase BDNF, in turn nurturing a bushier neuron than traditional antidepressants. Using fluorescent nano-spy chemicals that glow in the dark, the team could see under the microscope that psychedelics rapidly spurred the neuron into action. With a single dose, LSD moved TrkB into dendritic spines—mushroom-shaped bumps that help neurons connect with each other—a marker for neuroplasticity.

Inside the hippocampus—the hub for learning, memory, and a regulator for mood—the drug boosted the number of newborn neurons in mice with just a single shot after four weeks. Neurogenesis, or the birth of new neurons, is a long-standing marker for antidepressant efficiency.

Here’s the crux: these neuroplasticity effects went away when the team genetically mutated TrkB. Going back to the paper analogy, it’s as if someone shredded one part of the paper so it can no longer catch onto the other.

In contrast, the high remained in mice without TrkB. Although we can’t ask a mouse whether it’s tripping, they do have a tell: multiple head jerks, as if they were head bobbing to the Grateful Dead. When the team gave them a shot that neutralizes serotonin, the mice came down.

Conclusion? LSD takes two highways in the brain: one, organized by BDNF and TrkB, boosts neural growth and neuroplasticity. The other unleashes serotonin, which helps reorganize neural networks but also triggers a trip.

Keeping Afloat

New neural growth is great. But does it mean anything?

The team put LSD to the test, pitting mice with a critical TrkB mutation—therefore lacking the ability to absorb BDNF—against their non-genetically-engineered control peers in several challenges.

The first involved a kiddie pool and gauged chronic stress. Mice are natural swimmers. They just don’t like doing it too much. Like being constantly yelled at by a swimming coach, their mood eventually becomes low. With one shot of LSD, the control mice rallied and thrived in their swim tests even a week after the shot. In contrast, those with a mutated TrkB couldn’t bounce back, giving up easily.

In another test mimicking post-traumatic stress disorder (PTSD) and anxiety, a single dose of LSD helped dampen fear in control mice for a specific traumatic environment. The effects lasted for at least four weeks. Mice with a mutated TrkB didn’t fare as well, retaining their anxiety and stress when put back into the same environment throughout the trial.

To be clear, LSD isn’t a magical shot. Similar to other antidepressants that help battle PTSD, it’s all about set and setting. “LSD alone does not bring about fear extinction, as extinction training is required to produce a sustained decrease” in behaviors normally associated with fear in mice, said the authors. In other words, don’t try this at home.

LSD and other hallucinogens have a long battle ahead to shed their stigma and be accepted as an antidepressant. But they have a cheerleader: esketamine, one form of the club drug special K, was approved as an antidepressant in 2019. However, in 2022, the FDA released an alert informing health professionals that other ketamine formulations may put patients at risk, spurring scientists to seek out chemicals with a similar effect but not the high. Taking a page out of the playbook, in the same year a team screened 75 million chemical compounds related to LSD for their antidepressant activity without hallucinations.

The new study hints at ideas to further reboot psychedelic medicine. Before being criminalized in the 1960s, the National Institute of Health funded over 130 studies exploring psychedelics’ potential for mental health. With AI-powered large-scale drug screening and modern biochemical techniques, we’re already in a brave new world.

We can now design a new era of antidepressants that trigger TrkB “with fast and long-lasting antidepressant action, but potentially devoid of hallucinogenic-like activity,” said the team.

Image Credit: Free Fun Art / Pixabay

Shelly Fan
Shelly Fan
Shelly Xuelai Fan is a neuroscientist-turned-science writer. She completed her PhD in neuroscience at the University of British Columbia, where she developed novel treatments for neurodegeneration. While studying biological brains, she became fascinated with AI and all things biotech. Following graduation, she moved to UCSF to study blood-based factors that rejuvenate aged brains. She is the co-founder of Vantastic Media, a media venture that explores science stories through text and video, and runs the award-winning blog Her first book, "Will AI Replace Us?" (Thames & Hudson) was published in 2019.
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