On April 18, 2026, President Donald Trump, flanked by podcaster Joe Rogan, among others, issued Executive Order (EO) 14401, which began by noting that current mental health treatments fail many Americans. Then, in a remarkable shift from 20^th-century tough-on-drugs policies, the federal order encouraged research on the use of psychedelics, especially ibogaine compounds (derived from a West African shrub), for mental health conditions. It also potentially fast-tracked the drugs’ approval and provided $50 million for state-run research efforts.

“It’s not nothing to set aside $50 million, but I see the importance of the executive order as primarily symbolic,” said LDI Senior Fellow Holly Fernandez Lynch, Associate Professor of Medical Ethics and Health Policy at the Perelman School of Medicine. “It shows that the White House is behind psychedelic research, which could be important for investors. That could lead to more research and development, and eventually that’s going to benefit patients.”

Some experts predict that analogs of psilocybin (“magic mushrooms”) and MDMA (“ecstasy”) will gain FDA approval within the next year or two. Ibogaine, a passion of Joe Rogan’s, is less likely to be approved because it is known to cause heart problems.

But caution may be warranted. “There’s a lot that we don’t know about psychedelic-assisted therapy,” said Heath D. Schmidt, a Professor in Penn’s Schools of Nursing and Medicine. “We should learn to walk before we run.”

Here are some of the “known unknowns” that may affect the future of therapeutic psychedelics.  

How Do Therapeutic Psychedelics Work?

Studies conducted in the last 20 or so years have suggested that psychedelics, usually psilocybin or MDMA, can be effective after one to three doses at reducing smoking, alcohol use, and opioid use, and at tempering anxiety, major depression, and post-traumatic stress disorder (PTSD) — conditions that can be intractable. The prevailing theory is that psychedelics increase the neuroplasticity of the brain, enhancing its ability to rearrange neural connections into new configurations.

“For instance, with substance use disorder, people tend to develop a cycle of rigid behaviors, habit-based decision-making in which the brain has been rewired to respond to triggers that induce drug use,” said Paul Regier, Research Assistant Professor of Psychiatry in the Center for Studies of Addiction at Penn. “Researchers suspect that psilocybin and most of the psychedelics create new synapses between neurons, creating connectivity between different regions of the brain that might not have been as connected before. This shakes things up, and the brain becomes more plastic. The patient can break the rigidity of substance use behavior and increase functionality associated with healthier types of decisions.”

Psychedelics work differently than antidepressants like selective serotonin reuptake inhibitors, or SSRIs, that are taken every day. “SSRIs treat your moods by blunting them, making it harder to access bad feelings,” said LDI Senior Fellow Dominic Sisti, Associate Professor of Medical Ethics and Health Policy and Psychiatry at the Perelman School of Medicine. “By contrast, psychedelics allow you to access those challenging emotions. You have a calm distance from them so that the experience is not overwhelming. People with PTSD say they were able to confront really horrible traumas and that such safe exposure helps to disarm those memories.”

How Good Are the Data on Psychedelics?

“Promising” is the word that often appears in commentaries on psychedelic research. “There’s a lot of limitations to the data that’s out there,” said LDI Senior Fellow Margaret Lowenstein, Assistant Professor of Medicine at Perelman.

“One problem is that much of our understanding relies on studies with small numbers of subjects,” added Regier.

Another serious issue is what to use as a placebo. “In earlier studies, it was clear which participants were on the psychedelic and which participants were on what amounted to be a sugar placebo control,” Schmidt explained. “Newer placebos include niacin, low-dose benzodiazepines, and smaller doses of the psychedelic being studied.”

Building more solid evidence in the future, said Regier, “is a matter of better blinding, more rigorous trials, bigger numbers, and replicability.”

Will the Federal Government Reclassify Psychedelics?

Since 1970, psychedelics such as LSD and psilocybin have been classified as Schedule I drugs, putting these nonaddictive medications in the most restrictive category, alongside heroin. “There are obstacles that are unique to studying Schedule I compounds,” Schmidt said, “but it can be done, and obviously it is done. But they do limit the ability to study these drugs, and that’s why you don’t see as much research as you might think there would be in this space.”

Regier is researching psilocybin as an adjunct to medications for opioid use disorder. “It took a year and a half just to get everything going. These drugs have limited abuse liability, so they probably don’t need to be Schedule I. It would be a big boost if the government rescheduled them,” he said.

The White House is on record as favoring rescheduling. Section 5 of EO 14401 states: “The Attorney General shall, in consultation with HHS, initiate and complete review of any product containing a Schedule I substance that has successfully completed Phase 3 clinical trials for a serious mental health disorder, so that rescheduling, if appropriate under 21 U.S.C. 811, may proceed as quickly as practicable.”  

However, Fernandez Lynch noted, the rescheduling would be product-specific. “For example, approval of a specific psilocybin formulation will not lead to rescheduling of all psilocybin mushrooms,” she explained.

Are Psychotherapists Necessary to Give Psychedelics?

Most current research on psychedelics involves some kind of professional support. “The standard protocol calls for two preparation sessions that are each typically one to two hours long, in which the patient works through what their goals are and what they’ll be experiencing with a therapist,” Regier said. “During the sessions with the drug, there are two professionals, a lead facilitator and a co-facilitator, at least one of whom has been through psychedelic-assisted therapy (PAT) training.

Medical staff are nearby, receiving updates on blood pressure and similar measures and ready to intervene if a problem arises. After the psychedelic session, the patient receives two integration sessions, an hour or hour-and-a-half each, in which they discuss how to meet the goals that were set up in the initial meeting, and how to integrate the experience into their lives.”

For Sisti, the availability of a therapist after the session is crucial, even if one wasn’t present during the session. “There’s a period of time when individuals are still malleable and still have the potential for a lot of change. I think it’s important that people have access then to psychotherapy,” he said.  

The problem is that the FDA approves products, not practices. For that reason, many drug companies are testing the effects of psychedelics without therapy. In a 2024 consensus statement in JAMA Open Network, a group of experts, including Sisti, considered how, in this situation, psychedelics could be labeled to promote safe and effective use: “For example, the label for buprenorphine sublingual tablets, which is used to treat opioid use disorder, specifies that it ‘should be used as part of a complete treatment plan to include counseling and psychosocial support,’” the article states.

A related question is who will prescribe the drugs. “Do we really want primary care physicians prescribing these things, or should it just be psychiatrists?” Fernandez Lynch asks.

Can Psychedelics Work Without the Trip?

Joseph Cichon, Assistant Professor of Anesthesiology and Critical Care at Perelman, runs a basic science laboratory that uses advanced microscopy and mapping to understand how psychedelics and other psychotropic drugs reshape neural circuits to alter consciousness, mood, and pain processing.

“If you understand how psychedelics work at the molecular, cellular, and circuit level, there’s a possibility that you can design drugs that lack the psychedelic trip or hallucinogenic properties,” he said.

Cichon is currently working with two scientists at the University of California, San Diego, Loren Looger and Kallol Bera, to remove the dissociative effects of the rapid-acting antidepressant ketamine, which is sometimes considered a psychedelic. Scientists elsewhere are working on psilocybin and LSD.

“For patients with major depression disorder, there’s a great fear that if you give them ketamine or psilocybin, that might push them in a direction that they’re not comfortable with,” Cichon said. “The treatment would require intense clinical monitoring. Wouldn’t it be great if you had another drug that was pretty clean with regards to any psychedelic effects but gave a similar therapeutic effect?”

This research direction has been met with some skepticism. “The subjective experience of being on psychedelics might be important for the treatment,” Regier said. “For substance use disorder, especially, you might need some sort of shakeup, a moment of clarity in which the patient thinks, ‘OK, this is it. I’m done.’ We’ll find out when we do head-to-head trials at the same dose.”

What Effect Will Politicization Have on Psychedelics?

Joe Rogan has claimed responsibility for steering the White House toward ibogaine, a shift that surprised many researchers in the psychedelic field because the drug has been associated with health risks and is not as well studied as psilocybin and MDMA. “It’s a pretty egregious step for the White House to direct the FDA with regard to specific products,” said Fernandez Lynch. “That level of politicization is pretty extreme.”

Of particular concern is the FDA Commissioner’s National Priority Voucher pilot program. Announced in June 2025, the program, which applies to all pharmaceuticals, promises an accelerated review — from the regular 10 months to one to two months — of products that meet one or more of five criteria, including domestic manufacturing and addressing a public health crisis.

The key concern is that “this process is totally discretionary for the FDA,” said Fernandez Lynch.

A week after the press event for EO 14401, the FDA announced that three psychedelic-focused companies would receive the vouchers: two related to psilocybin as a treatment for severe depression and one for a metabolite of MDMA to treat PTSD.  

Fernandez Lynch views the rapid reviews as problematic. “The FDA does not have a lot of experience with psychedelics, which are challenging to study. Can it legitimately review them in one or two months?” she asked.

Another issue is that these resource-intensive efforts may displace reviews of other, possibly more urgent applications. Finally, “vouchers could taint the drug in the sense that people may wonder if it got approved because of the science or because the White House liked it,” Fernandez Lynch said.

However, despite all the limitations, scientists are optimistic about the future of psychedelics. “I think it’s going to be really exciting,” Lowenstein said.

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For Further Reading

• Cohen, I. Glenn, Holly Fernandez Lynch, and Amy L. McGuire. “The Psychedelic Therapies Executive Order.” JAMA, July 1, 2026. https://doi.org/10.1001/jama.2026.11892.
• Psychedelic drugs get the FDA fast-track (Holly Fernandez Lynch, April 2026 POLITICO Interview)
• McGuire, Amy L., I. Glenn Cohen, Dominic Sisti, Matthew Baggott, Yuria Celidwen, Neşe Devenot, Sabrina Gracias, et al. “Developing an Ethics and Policy Framework for Psychedelic Clinical Care: A Consensus Statement.” JAMA Network Open 7, no. 6 (June 4, 2024): e2414650. https://doi.org/10.1001/jamanetworkopen.2024.14650.
• Pennsylvania’s Cannabis Wave Is Already Here — And Our Mental Health System Isn’t Ready (Dominic Sisti, August 2025 op-ed in the Philadelphia Citizen)

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