Hope for Depression and Other Diagnoses with Psychedelics

Imagine unremitting despair, 24-7, minimally responsive or totally unresponsive to medication or therapy. Just endless depression. This is a problem for at least a third of adults with depression, which is why some experts have turned to psychedelic drugs as a possible answer for intractable depression and other psychiatric disorders.

HHS Director Robert F. Kennedy Jr. and Casey Means, President Trump’s choice for Surgeon General, have publicly endorsed psychedelic therapies. Kennedy said of people with treatment-resistant depression, “This line of therapeutics has tremendous advantage if given in a clinical setting, and we are working very hard to make sure that that happens within 12 months.”

Another key regulatory agency is the Food and Drug Administration. FDA Commissioner Marty Makary indicates the agency will pursue “expeditious and rapid review” of psychedelic treatments, helping to reduce regulatory hurdles.

Early trials of psychedelics have shown significant depressive symptom reduction in a remarkable two hours. Companies like atai Life Sciences and Beckley Psytech are developing fast-acting, short-duration compounds like BPL‑003, available in a nasal spray. Following promising trial data in July 2025, atai Life Sciences' stock jumped more than 20 percent. Analysts predict BPL‑003 could follow in the footsteps of Johnson and Johnson’s Spravato (an intranasal ketamine FDA-approved for treatment-resistant depression) and become a billion-dollar drug. However, in a recent meta-analysis in JAMA of control treatment outcomes in trials of psilocybin, SSRIs, or esketamine for depression, participants receiving control treatment in psilocybin trials had significantly less improvement in depression ratings than participants receiving control treatment in trials of SSRIs or esketamine.

The Nation’s Experts' Insights

New York University's Joshua S. Siegel, M.D., Ph.D., is a national expert on psychedelics and psychiatry, and his psilocybin research has demonstrated not only that psychedelics work but how they exert beneficial psychiatric effects. Siegel hypothesizes psilocybin temporarily dismantles entrenched or default brain patterns, enabling increased brain flexibility—or a “reset.”

In Siegel’s study, precision functional mapping was performed on healthy adults through 18 fMRI sessions, including baseline, active, and post-dosing scans. The researchers compared the effects of 25 milligram psilocybin to 40 milligram methylphenidate used as a placebo. They found greater acute disruption, by threefold, in functional connectivity under psilocybin versus methylphenidate.

The researchers discovered that psilocybin causes a persistent weakening in the brain’s anterior hippocampus default mode network connectivity, lasting up to three weeks. Said Siegel, “The longer-term consequence is that one 25 milligram psilocybin dose makes the brain more flexible and potentially more able to come into a healthier state.”

New Magic Mushroom Clinical Trials

In a Phase 3 trial, 258 participants with treatment-resistant depression participated across 32 sites in the United States. In this randomized, double-blind, placebo-controlled study, investigators aimed to assess the efficacy and safety of a single dose of COMP360 25 milligrams versus placebo for reducing symptom severity in TRD. A 25 milligram dose of COMP360 psilocybin (synthetic psilocybin) showed a statistically significant and clinically meaningful reduction in treatment-resistant depression symptom severity compared to placebo.

DMT and 5-MeO-DMT Clinical Implications and Outlook

The Sonoran Desert toad secretes a hallucinogenic substance, 5-MeO-DMT. This venom can be collected, dried, and smoked or vaporized to experience psychedelic effects. Scientists are working with synthetic formulations of 5-MeO-DMT. Studies suggest 5-MeO-DMT may lead to rapid and sustained improvements in depression. In addition, recent clinical trials sponsored by pharmaceuticals tested vaporized DMT (N,N‑Dimethyltryptamine) inhaled by patients with treatment-resistant depression. On July 1, 2025, Beckley Psytech and atai Life Sciences shared data from a Phase 2b study on intranasal 5-MeO-DMT (BPL-003) in treatment-resistant depression. The short-acting psychedelic, delivered alongside psychological support, caused a rapid and significant antidepressant effect. Response was rapid; up to 50 percent of participants recovered and maintained remission after one month.

If 5-MeO-DMT (BPL-003) continues to prove safe and effective, the compound could be a cheaper alternative to psilocybin and LSD, which are longer-acting and assumed to be more expensive to administer.

Ibogaine Development and Clinical Trials

Another psychedelic substance, ibogaine, was recently discussed by me. No natural ibogaine product has been approved. The first ibogaine-like drug is likely to be a cardio-safer analog, such as GM‑3009 or 18-MC, for release in 2027–2028 if safety profiles hold. In June 2025, Texas allocated $50 million to support FDA-approved ibogaine trials for opioid use disorder, PTSD, TBI, and other conditions. The goal of this investment is to ensure Texans reap the economic benefits from an ibogaine treatment program, not a pharmaceutical company. The investment entitles Texas to at least 20 percent of any successful ibogaine drug resulting from the trials, with a quarter of revenue allocated to a fund for state veterans. This places Texas as a national leader in ibogaine research, with state–pharma–university partnerships underway.

Psychedelics Essential Reads

The Drugs Meant to Induce Madness, a Review

After an Executive Order on Psychedelics, What Comes Next?

LSD for GAD, ADHD, and Alzheimer’s

LSD research in generalized anxiety disorder was recently reviewed by me.

MDMA

Completed multiple Phase 3 PTSD trials with MDMA (ecstasy) showed remission in up to 71 percent of subjects. However, the FDA rejected the drug application in August 2024 due to concerns over data integrity, unblinding, and safety. A new Phase 3 trial is required and expected to take two years; the revised approval timeline is pushed into 2027–2028.

Other Treatments for Depression, like Spravato (Esketamine)

While not a psychedelic, per se, the FDA approval of esketamine nasal spray became a model for other new treatments, some of which might be drugs of abuse. Esketamine was recently approved as a monotherapy (without other oral antidepressants). The new multicenter, double-blind randomized clinical trial of adults with treatment-resistant depression was described in JAMA Psychiatry. Esketamine nasal spray caused a robust antidepressant effect in severe depression compared to placebo. Direct comparison of esketamine and transcranial magnetic stimulation to psychedelics is necessary to help determine what is first, second, or third in the treatment algorithm for treatment-resistant depression.

Most Likely Psychedelic to Succeed First: Psilocybin

Based on current public data and clinical status, psilocybin is the most likely candidate to reach FDA approval first. Experts are currently awaiting additional Phase 3 data—likely in 2026. If positive, psilocybin could be FDA-approved and available by 2027.

But 5-MeO-DMT research is progressing, currently being tested by British psychedelic drug developer Beckley Psytech and atai Life Sciences as treatment for depression, alcohol use disorder, and anxiety. In June 2025, Atai and Beckley announced their intention to merge and pool resources to get their candidate psychedelics approved and on the market.