Psilocybin, a naturally occurring psychedelic compound found in “magic mushrooms,” has been touted as a potential game-changer for depression and other psychiatric disorders.

Over the past two decades, more than 130 clinical trials of psilocybin-based therapies have been conducted. Yet not a single agent has been green lit by the FDA.

But that could change in the near future. A number of experimental psilocybin-based drugs are in the pipeline — with one — maybe two — predicted to reach the FDA in the next 1 or 2 years.

Early work conducted in the 1950s and 1960s explored the potential use of psilocybin as a tool for psychotherapy, substance-use treatment, and exploration of consciousness. That research pretty much dried up after psilocybin was placed into Schedule I in the US in 1970 under the Controlled Substances Act.

Yet, controlled, university-based research on psilocybin resumed in the early 2000s. These studies use carefully screened patients, standardized doses, and psychological support before, during, and after the psilocybin session.

To date, small clinical trials have reported potential benefits for multiple psychiatric conditions, including treatment-resistant depression (TRD), severe anxiety and alcohol use disorder, posttraumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), and end-of-life distress.

How Does Psilocybin Work?

“That is a question that is still under active investigation and that there are no definitive conclusions yet, which is common across much of psychiatric pharmacology,” said George Greer, MD, psychiatrist, and president of the Heffter Research Institute a nonprofit that supports research into psychedelics and located in Santa Fe, New Mexico.

Psilocybin itself is a prodrug — after ingestion it’s converted into psilocin, the compound that produces psychoactive effects. Psilocin is a potent serotonin (5-HT) receptor agonist, especially at the 5-HT2A receptor, abundant in brain regions involved in mood regulation, sensory processing, sense of self, and cognitive flexibility.

Greer explained that psilocybin — like most classic psychedelics — activates the serotonin 2A (5-HT2A) receptor, which influences a wide network of connected neurons and triggers complex downstream effects in the brain. He noted that serotonin pathways are also implicated in depression as demonstrated by the clinical effectiveness of SSRI.

Functional MRI studies have shown that psilocybin reduces activity and connectivity in the default mode network, which is overactive in many psychiatric conditions including depression, anxiety, and OCD. Psilocybin has also been shown to promote neuroplasticity.

Psilocybin isn’t simply a “chemical fix.” Its therapeutic effects appear to arise from the combination of biochemical effects, psychological experience, and therapeutic context.

Unlike traditional antidepressants that require daily dosing, psilocybin can produce rapid symptom improvement that can persist for weeks or even months after a single session, suggesting that psilocybin may prompt a broader psychological shift rather than simply altering neurotransmitters.

It may help patients view their thoughts from a new vantage point, experience emotional breakthroughs, and reassess long-held beliefs and behaviors — changes that could enhance the impact of psychotherapy.

Participants in psilocybin trials have also described mystical experiences and research has shown that the intensity of these experiences correlates with long-term symptom improvement, suggesting the subjective experience is part of the therapeutic mechanism.

What’s in the Pipeline?

Several psilocybin-based therapies are now being evaluated in phase 2 and 3 trials.

“I think we’re all very hopeful that meaningful and impactful data might come out of one of the psychedelics in development, with the near term readouts being in major depressive disorder (MDD),” Roger McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, Toronto, Ontario, Canada, told Medscape Medical News.

Compass Pathways appears to be the furthest along in developing its investigational synthetic psilocybin formulation, COMP360. The therapy, delivered with structured psychological support, received FDA breakthrough therapy designation in 2018.

In a phase 2b clinical trial of 233 patients with TRD, a single 25-mg dose of COMP360 psilocybin plus psychological support was associated with a highly statistically significant reduction in depressive symptoms after 3 weeks (P < .001) that lasted for up to 12 weeks.

In addition, two pivotal phase 3 trials of COMP360 for treatment-resistant depression are underway. One is evaluating the safety, efficacy, and tolerability of a single dose, whereas the other is assessing the same outcomes with two doses.

Positive topline results from one of the phase 3 trials (COMP005) that was reported earlier this year showed a highly statistically significant and clinically meaningful reduction in symptom severity as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) after administration of a single 25-mg dose (P < .001).

After reporting positive COMP005 results, completing enrollment in the phase 3 COMP006 study, and meeting with the FDA, Compass Pathways announced it will move its COMP360 commercialization timeline forward by 9-12 months and plans to file a new drug application late next year.

COMP360 is also under evaluation for PTSD and anorexia nervosa. In a phase 2 study of 22 adults with PTSD, a single supported 25-mg dose was well tolerated and yielded rapid, lasting improvement.

In a study of 10 women with anorexia nervosa, 40% had clinically meaningful reductions in eating-disorder psychopathology after a single COMP360 dose.

At the same time, the Usona Institute — a nonprofit research organization in Madison, Wisconsin — has developed a pharmaceutical-grade synthetic psilocybin formulation that earned FDA breakthrough therapy designation for MDD in 2019.

In a phase 2 randomized controlled trial of 104 adults with MDD, a single 25-mg oral dose of psilocybin plus psychological support produced a large and rapid antidepressant effect that was sustained over 6 weeks compared with niacin placebo plus support. 

The Usona Institute is now leading a phase 3 randomized, placebo-controlled trial, uAspire, to evaluate the efficacy and safety of its psilocybin formulation for MDD in about 240 adults.

Cybin Inc is also getting in on the game. The company is developing and testing CYB003 — a proprietary deuterated psilocin molecule, which has breakthrough therapy designation for the adjunctive treatment of MDD.

In a phase 2 trial, two 16-mg doses of CYB003 administered 3 weeks apart, as an adjunct to ongoing antidepressant therapy, was linked to a 71% remission rate at 1 year. 

At 12 months, the mean change from baseline in MADRS total score was nearly 23 points among patients who received the two 16-mg doses. The phase 3 program for CYB003 is now underway and includes two randomized, placebo-controlled trials plus an extension study, with topline results expected in mid-2026.

Greer said he is confident psilocybin could be approved in just over a year, while acknowledging this path to approval is “unprecedented” and that unforeseen challenges could arise.

What Are the Barriers to Implementation, Access?

McIntyre noted that the FDA’s ruling on psilocybin-assisted therapy may rest on whether it applies the same methodological standards used in its review of midomafetamine-assisted therapy, which the agency did not approve last year due to insufficient evidence.

If a psilocybin-based therapy is approved, implementation challenges “become the reality and will likely influence the impact that these treatments may have on persons with lived experience,” McIntyre said.

He noted that a treatment can only face so many regulatory hurdles before its potential impact is diminished.

As one example, McIntyre said the FDA will likely require a risk evaluation and mitigation strategy (REMS) for psilocybin-based therapy, adding some regulatory complexity. Even so, he noted that a REMS is not inherently a barrier, citing esketamine nasal spray (Spravato), which also requires a REMS yet has grown to more than $1 billion in annual sales with thousands of certified clinics across the country.

He noted that the larger hurdle may be the need for substantial psychotherapeutic support around each session.

“If indeed the FDA requires that, it’ll frankly be a deal breaker for just about all clinics,” he said, adding that the vast majority of clinics are not in a position to provide two therapists for each session lasting 4-8 hours.

The high cost of psilocybin-assisted therapy stems largely from the delivery model rather than the compound itself. Oregon — the only state with a regulated psilocybin services framework — allows licensed centers to set their own prices, and published rates often start around US $1200 per individual session.

For example, one licensed center lists all-inclusive sessions beginning at US $1050-$1200. Similarly, an independent pricing tracker from Psychedelic Alpha, an analytics platform monitoring the psychedelic-medicine sector, reports session costs ranging from roughly US $1000 to more than US $5000, with some multi-day packages priced higher.

Given these challenges, McIntyre said he is more optimistic about emerging nonpsychedelic or minimally hallucinogenic compounds, which do not induce a trip and may lessen the need for extensive psychotherapeutic support. Several such agents are now moving into phase 2 trials.

He added that another key issue is the cost-effectiveness of psilocybin treatment, which he expects will receive significant scrutiny.

“Without a realistic cost-effectiveness estimate that is competitive relative to other agents, psychedelics will not be implemented at scale, greatly reducing their societal impact,” McIntyre and colleagues wrote in a recent paper addressing psilocybin implementation challenges published in The American Journal of Psychiatry.

The reimbursement model for psilocybin-based therapy is another “known unknown,” McIntyre said.

What Challenges Remain?

Although psilocybin-based therapy is not yet legal in the US under federal law, states like Oregon, Colorado, and New Mexico have moved to expand access to psilocybin treatment.

As psilocybin-based therapies move closer to potential integration into mainstream psychiatric care, the US National Network of Depression Centers Task Group on Psychedelics and Related Compounds has issued a consensus statement outlining both the therapeutic promise of psilocybin and the significant gaps that must be addressed before widespread adoption.

The group, led by researchers with the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, emphasized the need to understand , especially amid emerging concerns such as a potential increase in suicidal ideation, risks for unmasking bipolar disorder andlong-term safety unknown effects related to drug-drug interactions.

The drug’s intense psychological effects demand heightened safeguards and more robust informed consent, the authors noted. They warned that scientific enthusiasm and public interest are outpacing the development of safety guidelines, infrastructure, and provider training. They urged standardized training, mandatory certification, and careful implementation planning before the therapy is widely adopted.

The group also cautioned that current clinical protocols are resource-intensive, costly, and difficult to scale — a combination that could undermine equitable access.