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Psychedelics in 2025 : Bottom line up front

Psychedelics in 2025: Psychedelic medicine in the US has reached a crucial inflection point as of May 2025, with ketamine firmly established in mainstream treatment, psilocybin progressing toward potential FDA approval, and MDMA facing regulatory setbacks. Ketamine received expanded FDA approval as monotherapy for treatment-resistant depression in January 2025, while psilocybin therapy is accessible through licensed service centers in Oregon and Colorado with COMPASS Pathways' Phase 3 trial results expected by mid-2025. MDMA faces additional years of development after the FDA rejected Lykos Therapeutics' application in August 2024. A patchwork of state regulations creates varied access models alongside significant hurdles at the federal level, with at least 36 psychedelics-related bills introduced across more than a dozen states in the 2025 legislative session.

 

Research status and major clinical trials

Psilocybin studies advance toward potential approval

COMPASS Pathways leads the most advanced psilocybin research program, conducting pivotal Phase 3 trials for treatment-resistant depression with results expected in Q2 2025. If successful, FDA approval could come as early as late 2025 or early 2026. Johns Hopkins researchers reported in late 2024 that psilocybin's antidepressant effects may last at least one year for some patients, with depression severity scores remaining low at 1, 3, 6, and 12 months post-treatment.

A landmark 52-week observational follow-up from COMPASS Pathways' Phase 2b trial (published March 2025) demonstrated that a single 25mg dose showed longer maintenance of antidepressant effects compared to lower doses. Other major research institutions conducting psilocybin studies include Usona Institute (Phase 3 uAspire trial for major depressive disorder), Yale University, University of Wisconsin, UCSF, and Emory University.

Research has expanded beyond depression to include anxiety disorders, PTSD, substance use disorders, anorexia nervosa, obsessive-compulsive disorder, and chronic pain conditions. Cybin's Phase 2 trial of CYB003 (a deuterated psilocybin analog) showed patients experienced robust and sustained improvement in major depressive disorder symptoms at 4 months, with 75% of participants receiving two 16mg doses achieving remission.

 

MDMA faces regulatory roadblocks

The FDA's rejection of Lykos Therapeutics' (formerly MAPS PBC) New Drug Application for MDMA-assisted therapy for PTSD in August 2024 represented a significant setback. Despite promising Phase 3 results published in Nature Medicine in 2023 showing 71.2% of participants no longer met PTSD criteria after treatment, the FDA requested additional trials addressing concerns about data integrity, study design, and safety.

Lykos Therapeutics has reorganized and is planning a new Phase 3 trial addressing FDA concerns, with resubmission not expected until at least 2026. The Department of Veterans Affairs launched its first MDMA studies in decades in 2025, with a $1.5 million grant funding trials at Brown University and Yale University focused on veterans with both PTSD and alcohol use disorder.

Several innovative trials combining MDMA with established therapeutic approaches are underway, including the STRONG STAR Consortium's trial combining a single dose of MDMA with massed Prolonged Exposure therapy for active-duty military personnel. Research centers leading MDMA studies include University of California San Francisco, Johns Hopkins University, VA San Diego Healthcare System, and various academic centers with established psychedelic research programs.

 

Ketamine achieves mainstream acceptance

Ketamine research continues to expand with 363 active trials, including approximately 49 Phase III and 107 Phase IV trials. The 2023 ELEKT-D trial, published in the New England Journal of Medicine, demonstrated that ketamine was non-inferior to electroconvulsive therapy for treatment-resistant depression, with 55.4% in the ketamine group showing significant improvement compared to 41.2% in the ECT group, with fewer cognitive side effects.

The Bio-K study reported in early 2024 that 52% of participants with severe treatment-resistant depression achieved remission after just three infusions of ketamine. A January 2025 study comparing intravenous ketamine to Spravato (esketamine) nasal spray found that IV ketamine showed higher efficacy but also more treatment-emergent adverse events.

Leading institutions conducting ketamine research include the National Institute of Mental Health, Yale University School of Medicine, University of Michigan Frances and Kenneth Eisenberg Depression Center, Massachusetts General Brigham/Harvard Medical School, and Johns Hopkins University.

 

Federal regulatory developments and FDA approval status

Psilocybin: Promising but still Schedule I

Psilocybin remains classified as a Schedule I controlled substance under federal law as of May 2025. It has received FDA Breakthrough Therapy designation for treatment-resistant depression (COMPASS Pathways, 2018) and major depressive disorder (Usona Institute, 2019). In March 2024, the FDA granted Breakthrough Therapy designation to Cybin's CYB003, a deuterated psilocybin analog, for adjunctive treatment of major depressive disorder.

No psilocybin therapy has received FDA approval as of May 2025. In June 2023, the FDA published its first draft guidance for industry on psychedelic drugs titled "Psychedelic Drugs: Considerations for Clinical Investigations," providing a framework for research and development. Based on current timelines, the earliest possible FDA approval for psilocybin therapy could come in late 2025 or early 2026, pending successful Phase 3 trial results.

 

MDMA: Rejected but not abandoned

MDMA remains classified as a Schedule I controlled substance as of May 2025. It received Breakthrough Therapy designation from the FDA for PTSD in August 2017, expediting its development and review process. Despite this designation, the FDA's Psychopharmacologic Drugs Advisory Committee voted 10-1 against recommending approval in June 2024, followed by the FDA's rejection in August 2024.

The FDA rejection cited concerns about study design and potential unblinding, reports of unreported adverse events, potential for misuse, ethical concerns including a documented case of sexual misconduct during a Phase 2 study, and questions about the therapeutic protocol used alongside MDMA. Lykos Therapeutics has committed to addressing these concerns, though a new approval attempt is likely years away.

 

Ketamine: Expanded approval in 2025

Ketamine remains classified as a Schedule III controlled substance under the Controlled Substances Act. The most significant regulatory development has been the January 21, 2025, approval of Spravato (esketamine) as a monotherapy for treatment-resistant depression. This makes it the first and only monotherapy specifically approved for this indication, no longer requiring concurrent use of an oral antidepressant.

The Spravato Risk Evaluation and Mitigation Strategy (REMS) program remains in effect in 2025 with stringent requirements: administration only in certified healthcare settings, patient enrollment in the REMS program, direct supervision by a healthcare provider, and at least 2 hours of monitoring after administration.

PharmaTher's proprietary ketamine formulation (KETARX) has a pending FDA approval with a goal date of June 4, 2025, for anesthesia, sedation, pain, and neurological indications. In February 2023, the FDA granted orphan drug designation to PharmaTher's KETARX for Rett Syndrome, a rare genetic neurological disorder.

 

State-level policy changes and legalization efforts

Psilocybin leads state-level reform

Oregon pioneered legal psilocybin services in 2023 through the Oregon Psilocybin Services Act. The program has been operational for over two years, with licensed facilitators providing psilocybin therapy in approved service centers. Colorado launched its regulated psilocybin therapy program in early 2025, with the first licenses for Medical Assisted Use issued in March 2025.

In April 2025, New Mexico Governor Michelle Lujan Grisham signed the Medical Psilocybin Act, establishing a therapeutic psilocybin program for patients with qualifying conditions. This marked the first state to enact psychedelics legalization through the legislative process rather than through a ballot measure.

As of the 2025 legislative session, more than 36 psychedelics-related bills have been introduced across more than a dozen states. New York, California, Iowa, Massachusetts, and Minnesota all have active legislation under consideration for various forms of therapeutic access to psychedelics.

 

MDMA regulation tied to federal approval

While no state has implemented a full MDMA therapy program due to the federal rejection in 2024, several states have enacted legislation in anticipation of eventual FDA approval:

  • Colorado passed HB 1344 in 2022, which automatically legalizes MDMA for medical use upon FDA approval
  • California Governor Gavin Newsom signed AB 1021 in 2023, allowing healthcare professionals to prescribe MDMA if rescheduled federally
  • Connecticut passed legislation in 2023 establishing a pilot program providing psychedelic-assisted therapy to eligible patients
  • Maryland created a state fund to provide "cost-free" access to psychedelics including MDMA for veterans with PTSD and traumatic brain injury
  • Utah passed Senate Bill 266 permitting two healthcare providers to offer MDMA therapy once federally approved

 

Ketamine access expands through clinics and telehealth

State-level regulation of ketamine clinics remains inconsistent across the United States in 2025. The estimated 500-750 ketamine clinics operating nationwide are primarily regulated through state medical and nursing boards rather than through ketamine-specific legislation.

The DEA has extended telehealth flexibilities for prescribing controlled substances through December 31, 2025, allowing continued telehealth prescribing of ketamine under certain conditions. At-home ketamine administration via telehealth has grown in popularity, though regulators have expressed concerns about safety and monitoring, with the FDA issuing warnings about compounded ketamine products in 2023.

Insurance coverage for ketamine therapy remains limited but is gradually expanding. Spravato enjoys the broadest coverage due to its FDA approval, with most major insurance companies offering some level of coverage when specific criteria are met. Traditional IV ketamine therapy remains largely uncovered by insurance due to its off-label status, with patients typically paying out-of-pocket ($600-$1,000 per infusion).

 

Recent breakthrough studies and applications

Psilocybin mechanisms and efficacy clarified

A 2024 study published in the Journal of Psychopharmacology showed that psilocybin therapy has potential as a treatment for depression in almost 400 participants, with evidence that repeated doses may have a consolidating effect. Johns Hopkins research demonstrated that psilocybin can alter the claustrum, an area of the brain believed responsible for setting attention and switching tasks, potentially explaining its therapeutic mechanism.

A 2024 Swiss clinical trial demonstrated that a single, moderate dose of psilocybin significantly reduced depressive symptoms compared to placebo for at least two weeks, with 54% of participants meeting remission criteria. New protocols have been developed allowing patients to remain on antidepressants during psilocybin therapy, unlike earlier trials that required medication discontinuation.

 

MDMA shows promise for dual diagnoses

The MAPP2 trial published in 2023 demonstrated efficacy across a diverse population, including ethnoracial minorities and individuals with comorbidities, addressing previous concerns about limited diversity in psychedelic research. The Brown/Yale VA studies initiated in 2024-2025 are the first to specifically target dual diagnosis of PTSD and alcohol use disorder with MDMA therapy.

Newer studies are exploring the efficacy of single-dose MDMA administration within compressed therapy timeframes (massed therapy), which could significantly reduce treatment time and resources if proven effective. The MDMA-facilitated Cognitive-Behavioral Conjoint Therapy study at VA San Diego represents an innovative approach treating veterans alongside their partners to address relationship effects of PTSD.

 

Ketamine's applications broaden

The 2023 ELEKT-D study established ketamine as non-inferior to ECT for treatment-resistant depression without the associated memory impairment, potentially repositioning ketamine earlier in the treatment algorithm for severe depression. Research at Harvard University using zebrafish models revealed in 2024 that ketamine's antidepressant effects may involve astroglia cells rather than just neurons.

Emerging evidence supports combining ketamine with psychotherapy, with several 2024 trials showing enhanced and prolonged benefits when ketamine administration is paired with structured psychotherapeutic approaches. Research teams at the University of Michigan and NIMH have made progress identifying blood-based biomarkers that may predict ketamine response, potentially allowing for more targeted treatment approaches.

 

Current approved medical uses and treatment targets

Psilocybin applications target mental health

While psilocybin has no FDA-approved medical uses as of May 2025, research focuses primarily on mental health conditions. Treatment-resistant depression is the most advanced research area, with Phase 3 trials nearing completion. Major depressive disorder is the target of multiple Phase 2 and Phase 3 trials, with promising results.

Other research areas include anxiety disorders (including generalized anxiety disorder and end-of-life anxiety), PTSD, anorexia nervosa, obsessive-compulsive disorder, substance use disorders, pain management (including chronic phantom limb pain and chronic low back pain), and Parkinson's disease with depression.

 

MDMA focuses primarily on PTSD

No MDMA treatments are currently FDA-approved, though PTSD remains the primary indication in ongoing research. The clinical trial model uses MDMA in conjunction with specialized psychotherapy, typically involving preparatory therapy sessions, 2-3 supervised 8-hour MDMA sessions spaced 3-5 weeks apart, integration therapy sessions following each MDMA session, and a total treatment duration of approximately 12-15 weeks.

Research into additional applications includes alcohol use disorder, social anxiety in autistic adults, treatment-resistant depression, and couples therapy for relationship healing when one partner has PTSD.

 

Ketamine established for depression and pain

Ketamine remains a Schedule III substance approved as an anesthetic since the 1970s. Spravato (esketamine) is FDA-approved for treatment-resistant depression (2019), major depressive disorder with suicidal ideation (2020), and as of January 2025, as monotherapy for treatment-resistant depression.

Ketamine is widely used off-label for depression, anxiety, PTSD, and chronic pain. A 2024 study in the New England Journal of Medicine found ketamine treatment as effective as electroconvulsive therapy for treatment-resistant depression with fewer side effects. Recent research supports extended-release oral formulations, potentially increasing accessibility.

 

Key organizations and research institutions

Psilocybin research led by diverse actors

Major pharmaceutical companies involved in psilocybin research include COMPASS Pathways (leading Phase 3 trials for TRD with COMP360 synthetic psilocybin), Cybin Inc. (developing CYB003, a deuterated psilocybin analog, for MDD), and MindMed (advancing psychedelic drug development, with focus on MM120, an LSD formulation, for anxiety disorders).

Prominent research institutes and universities include Johns Hopkins Center for Psychedelic and Consciousness Research (pioneer in the field with extensive publications and ongoing trials), Usona Institute (nonprofit conducting clinical trials for psilocybin in MDD), Heffter Research Institute (key organization sponsoring multiple clinical trials), NYU Grossman School of Medicine, University of California San Francisco, Yale University, and Emory University Center for Psychedelics and Spirituality.

 

MDMA development spearheaded by nonprofits

Lykos Therapeutics (formerly MAPS Public Benefit Corporation) is the primary company pursuing FDA approval for MDMA-assisted therapy, sponsoring Phase 3 trials and responsible for the NDA submission. The Multidisciplinary Association for Psychedelic Studies (MAPS) is the non-profit research organization that incubated Lykos, founded in 1986 by Rick Doblin to advance psychedelic medicine.

The VA Office of Mental Health and Suicide Prevention has begun funding and conducting MDMA research within the VA system as of 2024-2025. The STRONG STAR Consortium is a national research network focused on treatment for military-related PTSD, now incorporating MDMA studies.

 

Ketamine research spans academia and industry

Major pharmaceutical companies involved in ketamine research include Johnson & Johnson/Janssen Pharmaceuticals (developers of Spravato), PharmaTher Holdings Ltd. (focused on developing KETARX for multiple indications), Celon Pharma (developing a dry powder inhaler formulation of esketamine), and Perception Neuroscience/atai Life Sciences (developing arketamine, with potentially fewer dissociative effects).

Prominent ketamine clinic networks include Ketamine Clinics Los Angeles, Field Trip Health, Mindbloom (a leading provider of at-home ketamine therapy via telehealth), and Ketamine Wellness Centers. Leading research institutions include the National Institute of Mental Health, Yale University School of Medicine (where original breakthrough research on ketamine for depression was conducted), University of Michigan, Massachusetts General Hospital/Harvard Medical School, and Johns Hopkins University.

 

Timeline of key regulatory developments (2023-2025)

2023: Guidelines established and applications submitted

  • March 2023: Publication of the ELEKT-D trial in NEJM, demonstrating ketamine's non-inferiority to ECT for treatment-resistant depression
  • June 2023: FDA issued first draft guidance on psychedelic drug development, providing a framework for research and clinical trials
  • September 2023: MAPP2 trial results published in Nature Medicine, confirming efficacy of MDMA-AT for moderate to severe PTSD in a diverse population
  • October 2023: FDA issues warning about potential risks of compounded ketamine products for psychiatric disorders
  • October 2023: California Governor Gavin Newsom signs AB 1021, allowing automatic prescription of MDMA and psilocybin if federally rescheduled
  • December 2023: Lykos Therapeutics submits New Drug Application to FDA for MDMA-assisted therapy for PTSD

 

2024: Major decisions and setbacks

  • January 2024: DEA increased aggregate production quota for psilocybin research to 20,000 grams
  • February 2024: FDA accepts Lykos Therapeutics' NDA for MDMA-assisted therapy with priority review
  • March 2024: FDA granted Breakthrough Therapy designation to Cybin's deuterated psilocybin analog for major depressive disorder
  • June 2024: FDA Advisory Committee votes 10-1 against recommending approval of MDMA-AT
  • August 2024: FDA issues Complete Response Letter to Lykos Therapeutics rejecting the MDMA NDA and requesting an additional Phase 3 trial
  • October 2024: COMPASS Pathways restructures to focus solely on psilocybin therapy
  • October 2024: FDA issues Complete Response Letter to PharmaTher regarding KETARX application
  • December 2024: DEA extends telehealth flexibilities for controlled substances through December 31, 2025

 

2025: New approvals and state-level momentum

  • January 2025: FDA approves expanded indication for Spravato (esketamine) as monotherapy for treatment-resistant depression
  • January 2025: Minnesota psychedelics task force submits final report
  • January 2025: Cybin advances CYB003 into Phase 3 testing for major depressive disorder
  • March 2025: COMPASS Pathways publishes 52-week follow-up results from Phase 2 trial showing durability of single 25mg dose
  • March 2025: Colorado issues first licenses for Medical Assisted Use of psilocybin
  • March 2025: PharmaTher submits response to FDA's Complete Response Letter for KETARX
  • April 2025: New Mexico governor signs bill establishing therapeutic psilocybin program
  • April 2025: Lykos announces plans for a redesigned Phase 3 trial with projected completion in late 2027

 

Barriers to wider therapeutic approval

Regulatory challenges remain significant

The federal regulatory landscape remains the most significant barrier to psychedelic medicine advancement. Most psychedelic substances, including psilocybin and MDMA, remain Schedule I controlled substances under federal law, categorized as having "no currently accepted medical use and a high potential for abuse."

The FDA's August 2024 rejection of Lykos Therapeutics' application for MDMA-assisted therapy for PTSD highlighted concerns with study design and "functional unblinding" where participants could easily tell whether they received the active drug or placebo, questions about the extent to which psychotherapy contributes to the treatment's efficacy versus the drug itself, and inadequate safety data and adverse event reporting.

Other regulatory hurdles include complex DEA requirements for research with Schedule I substances, the need for multiple regulatory approvals across different agencies, lack of clarity on how psychotherapy components will be integrated into approval frameworks, and the requirement for additional large-scale Phase 3 trials.

 

Scientific and financial barriers compound regulatory hurdles

Designing adequately blinded studies is particularly difficult with psychedelics due to their pronounced subjective effects. The relationship between drug effects and accompanying psychotherapy remains difficult to quantify scientifically. Limited data exists on long-term safety and efficacy beyond initial treatment periods, with some research reporting negative long-term psychological responses in a small percentage of users.

Current models for psychedelic-assisted therapy are resource-intensive, with estimated costs of $10,000-$15,000 per treatment course for MDMA-assisted therapy due to extended sessions and the need for specialized therapists. Insurance coverage for psychedelic therapy is extremely limited, with Spravato being the only FDA-approved psychedelic-adjacent treatment covered by some insurers.

 

Expert perspectives on the future

Measured optimism despite setbacks

Leading researchers remain cautiously optimistic about psychedelics' future in mainstream medicine despite regulatory challenges. Dr. Lynn Marie Morski, president of the Psychedelic Medicine Association, expressed optimism in early 2025: "It seems like this year is starting with an acknowledgement by some of the mainstream medical associations that...psychedelic medicine is a legitimate form of therapy."

Following the FDA's rejection of MDMA, Dr. Rachel Yehuda, director of the Center for Psychedelic Therapy Research at Icahn School of Medicine at Mount Sinai, noted that the decision "raises questions about how to keep the work going," reflecting the field's determination to address regulatory concerns.

 

Regulatory pathways gradually emerge

Expert predictions for psychedelic medicine development suggest that following the FDA's 2024 rejection, MDMA approval could be pushed to 2027-2028 at the earliest. Compass Pathways is positioned as the closest to potential FDA approval for psilocybin therapy for treatment-resistant depression, with results from their first Phase 3 trial expected in summer 2025. If successful, they could file for approval in late 2025 or early 2026.

Several companies are developing "second-generation" psychedelic compounds that retain therapeutic benefits while minimizing or eliminating hallucinogenic effects, potentially expanding the patient population and use cases. Comprehensive training programs for therapists are essential, with efforts already underway across multiple institutions including California Institute of Integral Studies, Fluence, UC Berkeley Center for the Science of Psychedelics, and InnerTrek.

 

Conclusion

The psychedelic medicine landscape in the United States as of May 2025 shows a field in transition, with significant advances alongside persistent challenges. Ketamine has firmly established itself in mainstream treatment with expanded FDA approval, while psilocybin continues to progress toward potential approval with strong clinical trial results. MDMA faces a longer regulatory path following the FDA's 2024 rejection, though research continues, particularly for PTSD treatment.

State-level initiatives have created an increasingly complex patchwork of regulations, with Oregon, Colorado, and New Mexico leading the way in establishing frameworks for psilocybin access. The accelerating pace of state legislation, with over 36 psychedelics-related bills across more than a dozen states in 2025 alone, signals growing acceptance and momentum. Despite regulatory hurdles, continued investment in research, infrastructure, and professional training indicates psychedelic medicine will likely become an increasingly significant component of mental healthcare in the coming years, particularly for difficult-to-treat conditions that have limited options in current treatment paradigms.

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