Psychedelic Drugs Are Rushing Towards Approval for Therapy. Here’s What’s Next

Psychedelics made their mark this year—not as counterculture party drugs, but as a new paradigm in mental health therapy.

In June, Australia became the first country to greenlight MDMA, popularly known as molly or ecstasy, and psilocybin, the active ingredient in magic mushrooms, to treat post-traumatic stress disorder (PTSD) and depression.

MDMA also inched closer to approval in the US for PTSD, thanks to positive results from a large multi-site, double-blind, randomized trial—the gold standard for testing drug safety and efficacy.

Meanwhile, psilocybin gained steam as a treatment for severe depression. A randomized, placebo-controlled trial in 104 adults found that a single dose of magic mushrooms dampened the symptoms of depression when combined with psychological support. The effects lasted at least six weeks with minimal side effects. Clinical trials are in the works to explore whether psilocybin and its derivatives can help patients cope with chronic lower back pain, tackle depression in bipolar disorder, and ease mental struggles in end-of-life care.

This year also saw magic mushrooms for therapy move ahead. Registered clinics in Oregon have already begun psilocybin treatments in patients with mental health disorders ranging from obsessive-compulsive disorders to PTSD—even though the drug isn’t federally approved and remains illegal.

In 2022, Oregon became the first state to legalize psilocybin therapy with strict regulations: The mushrooms are carefully controlled for potency and quality and need to be taken under supervision. The guidelines offer a blueprint for other states—such as Colorado, which also decriminalized psilocybin for potential therapeutic use.

Yet one glaring problem remains. Despite promising clinical results, no one knows exactly how psychedelic drugs work in the brain. Examining their actions on brain cells isn’t just an academic curiosity. It could give rise to variants that maintain antidepressant properties without the high. And because hallucinogens substantially alter our perception of the world, they could be powerful tools for investigating the neurobiology behind consciousness.

Lucy in the Sky With Brain Cells

Mind-altering drugs are “fabulously dirty,” in that they act on multiple targets across the brain, with each activating different types of neurons in diverse regions.

However, they share similarities. For example, most psychoactive drugs regulate serotonin, a brain chemical involved in mood, appetite, memory, and attention.

This year, scientists found another common theme—psychedelics seem to “reset” the brain to a more youthful state, at least in mice. Like humans, mice have an adolescent critical period, during which their brains are highly malleable and can easily rewire neural circuits, but the window closes after adulthood.

An earlier study showed that MDMA reopens the critical window in adult mice, so that they change their “personality.” Mice raised alone are often introverted and prefer to keep to themselves in adulthood. A dose of MDMA increased their willingness to snuggle with other mice—essentially, they learned to associate socializing with happiness, concluded the study.

It’s not that surprising. MDMA is well-known to promote empathy and bonding. The new study, by the same team, extended their early results to four psychedelics that don’t trigger fuzzy feelings—LSD, ketamine, psilocybin, and ibogaine. Similar to MDMA, adult mice raised alone changed their usual preference for solitude when treated with any of the drugs. Because habits are hard to change in adulthood—for mice and men—the drugs may have reopened the critical period, allowing the brain to more easily rewire neural connections based on new experiences.

People with depression often have rigid neural networks that lock them into non-stop ruminations and dark thoughts. Psychedelics could potentially be a “master key” that helps brain networks regain their fluidity and flexibility.

Surprisingly, despite vastly different chemical structures, all the tested psychedelics activated a brain protein called brain-derived neurotrophic factor. A nutrient for brain cells, the protein helped brain regions involved in memory and mood give birth to new neurons. It also restored damaged neural branches, so neurons could better connect into functional networks.

Classic antidepressants such as Prozac also activate the protein, but psychedelics are far more effective. It could be why they rapidly relieve depressive symptoms within hours, whereas conventional alternatives often take months.

That said, being high all the time is hardly practical.

Another study suggests that it might be possible to separate a drug’s mind-bending and mood-boosting effects. By studying brain networks in mice tripping on LSD, the researchers pinpointed a key hub for the drug’s anti-depressant effects. Genetically deleting the protein hub reduced anti-depressant effects, but kept the high (on acid, mice bob their heads nonstop as if jamming to the Grateful Dead). The results suggest it may be possible to develop LSD variants that skirt unwanted hallucinations but keep their rapid antidepressant properties.

These are just early results. But psychedelic research is gaining a new ally—artificial intelligence. Algorithms that predict protein structure, combined with rational drug design, could generate psychedelics that retain their psychiatric benefits without the high.

Machine learning could also further help decipher their effects on brain activity. For example, a collaboration between McGill University in Canada, the Broad Institute at Harvard and MIT, and other institutions is using AI to explore how hallucinogens alter different chemical systems in the brain.

The method is outside-the-box: The study designed an algorithm that analyzed 6,850 “trip reports” from people who took a range of 27 different drugs and cataloged their subjective experiences in everyday language. The AI extracted commonly used words for any given substance and linked them to brain chemical systems across brain regions that are likely affected by that particular drug. In other words, the AI reliably translated real-world experiences into potential chemical changes in the brain for researchers to explore. A similar tool could link drug-induced changes in consciousness to different brain regions.

A Regulatory Sea Change

Despite growing enthusiasm, hallucinogens and empathogens—such as MDMA—remain federally illegal. The Drug Enforcement Agency classifies them as Schedule I, meaning the agency considers them drugs without known medical uses and high risk of abuse.

However, federal regulators are gradually warming up to their potential.

In June, the Food and Drug Administration released draft guidance on how to conduct clinical trials using psychedelic drugs—giving the field a tentative nod. The agency has already approved a version of ketamine for treatment-resistant depression and granted MDMA and psilocybin breakthrough therapy status to accelerate their development. Even Congress is on board. This year, it passed bills allowing the Department of Veteran Affairs to study psychedelics for veterans’ mental health.

Acceptance is also growing across society. A small poll by the UC Berkeley Center for the Science of Psychedelics found over 60 percent of 1,500 surveyed participants supported legalizing psychedelics for therapy, as long as they’re regulated.

This year was a landmark year for psychedelic therapy. While promising, the results are still early. Given the drugs’ tumultuous history, researchers and practitioners are carefully moving forward with guidelines on best therapeutic practices (such as what to do when a patient suffers a bad trip). With at least 260 registered clinical trials in the works, next year is poised to continue psychedelic drugs’ foray into mental health.

Image Credit: Marcel StraußUnsplash

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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