Introduction
Mental illness has an enormous impact on patients, the healthcare system, and society. More than 1 in 5 adults in the United States (US) experience mental illness each year and 1 in 20 experience a serious mental illness each year.i In people ages 10-24, suicide is the second leading cause of death. Further, substance use disorder treatment continues to be a public health challenge; in 2024, it was estimated that in the previous year 48.4 million Americans aged 12 or older had struggled with a substance abuse disorder.ii
The limitations of conventional therapies for treatment-resistance conditions led to renewed interest in psychedelics as potential treatments for a variety of mental health conditions. There continues to be an unmet medical need for patients who suffer from mental illnesses. If effective and used wisely, these novel treatments have the potential to change the treatment paradigm for various mental health conditions.
On April 18, 2026, the president signed an Executive Order aimed at accelerating access to treatments for patients with serious mental illness. The order provides a path for the Food and Drug Administration (FDA) to accelerate the approval of drugs that have received Breakthrough Therapy designations for treating serious mental illnesses and meet the National Priority Voucher program. In addition, the order directs the FDA and Drug Enforcement Agency (DEA) to develop a pathway for eligible patients to access psychedelic drugs under the Right to Try Act1 and has allocated $50 million in funding to support and partner with State governments that are developing programs to advance psychedelics drugs for serious mental health conditions.iii
As of June 8, 2026, over 600 studies were listed on clinicaltrials.gov for psychedelic drugs. Typically, the psychedelic classes include tryptamines (psilocybin, psilocin (active metabolite of psilocybin, dimethyltryptamine (DMT)); ergolines (LSD (d-lysergic acid diethylamide); phenethylamines (midomafetamine, mescaline) and dissociative drugs (ketamine, esketamine, ibogaine).iv Yoa et al., performed a systematic review and analysis of clinical trials published after 1960 on the efficacy and safety of psychedelics for mental health disorders. Their finding suggests that although efficacy may vary due to the difference in the drug or trial design the psychedelics; psilocybin, LSD, ayahuasca and midomafetamine had a therapeutic effect on anxiety and depression and possibly other mental health disorders such as post-traumatic stress syndrome and alcohol use disorders.v
Approved Products
Ketamine and Esketamine
Ketalar®(ketamine hydrochloride) was approved by the FDA in 1970 as a sole anesthetic for diagnostic and surgical procedures that do not require skeletal muscle relaxation. In the 1980s the use of ketamine as a party drug increased and in 1999, the US made ketamine a Schedule III controlled substance. In 2000, researchers at Yale were the first to publish the results of a small placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of ketamine in patients with major depression. They concluded that subjects with depression had significant improvement in depressive symptoms after ketamine infusion, but not after the placebo infusion, suggesting a therapeutic role of ketamine in the treatment of depression.vi This research laid the foundation for the development of esketamine, the S-enantiomer of racemic ketamine.
It was not until 2019 that Spravato® (esketamine) was approved in conjunction with an oral antidepressant for the treatment of treatment-resistant depression. It was approved with a Risk Evaluation and Mitigation Strategy (REMS) to mitigate the risks of serious adverse outcomes resulting from sedation and dissociation caused by Spravato administration, as well as abuse and misuse.vii In 2020, treatment of depressive symptoms in adults in major depressive disorder with acute suicidal ideation or behavior in conjunction with an oral antidepressant was added. In 2024, the Spravato REMS was modified to include the risk of respiratory depression and in 2025, the indication was expanded to include Spravato as monotherapy for treatment resistant depression. Ketamine is currently being studied for the treatment of suicidal depression and severe alcohol use disorder.
Products Under Investigation: Promising but not yet approved by FDA
Psilocybin
Psilocybin is in the class of drugs that act primarily as an agonist of the 5-HT2A receptor and can produce changes in sensory perception as well as thoughts and moods.4 Yao’s systematic review and metanalysis focused on Lysergic acid diethylamide (LSD), ayahuasca, psilocybin and 3,4-methylenedioxymethamphetamine (MDMA). Psilocybin had the largest number of published trials on treating mood disorders (N = 28), followed by ayahuasca (N = 7) and LSD (N = 6) with psilocybin showing the strongest therapeutic effect among four psychedelics.iii Psilocybin is currently being studied as therapy for treatment resistant depression, major depressive disorder, and Post Traumatic Stress Disorder (PTSD).viii,ix
On April 25, 2026, FDA announced that they were issuing national priority vouchers (NPVs) to three companies studying psychedelics to treatment serious mental health disorders. Psilocybin received 2 of the 3 vouchers, one for treatment-resistant depression (Compass Pathways) and the second for major depressive disorder (Usona Institute).x
3,4-methylenedioxymethamphetamine (MDMA)
The drug, 3,4-methylenedioxymethamphetamine (MDMA) also known as midomafetamine, acts on brain cells that use chemical serotonin and may result in increased energy, altered perception of time and space, and enhanced enjoyment of tactile experiences. MDMA is currently being studied in areas such as PTSD and alcohol use disorder.xi
Lykos Therapeutics had submitted an application for the approval of midomafetamine for the treatment of PTSD. In 2024, FDA issued a complete response letter for the application for MDMA-assisted therapy for PTSD citing that the “application does not provide substantial evidence of effectiveness or establish the safety of [the] product to support the approval of midomafetamine for the treatment of PTSD”.xii, xiii
The complete response letter marked a setback for clinicians and patients waiting for another therapeutic option for the treatment of PTSD. However, in December 2024, the US Department of Veterans Affairs (VA) announced they were funding a study to evaluate MDMA-assisted therapy for PTSD and alcohol use disorder among veterans.xiv This is the first time since the 1960’s that the VA has funded studies on psychedelics in veterans. Emory University and University of Texas Health Science Center at San Antonio are collaborating in this clinical trial aimed at the treatment of PTSD, this is supported by US Department of Defense through a $4.9 million grant.xv This research may provide additional information that could support FDA approval.
Methylone
Methylone was synthesized in 1996.xvi It is a structural analog of MDMA, both are monoamine reuptake inhibitors as well as potent releasers; however, methylone is reported to have no activity at the 5-HTsA receptors. Poyatos et al., evaluated the acute pharmacological effects and abuse effects of methylone to MDMA in two small studies, one randomized, double-blind, placebo-controlled, crossover clinical trial and the other an observational study.xvii,xviii Subjects reported similar subjective effects (intensity, stimulated, high, content, drunkenness) and similar objective effects (increases in blood pressure, heart rate) were observed for MDMA and methylone. Although methylone appeared to have less psychostimulant and less empathogenic than MDMA, the abuse potential of methylone may be comparable to that of MDMA. Prelincal studies suggest methylone has an antidepressive effect. xix,xx Methylone is currently in Phase 2 trials and being studied for PTSD. Transcend Therapeutics received Breakthrough Therapy Designation in July 2025 and is the third company that is developing a psychedelic to receive an NPV from FDA. 3
N,N-Dimethyltryptamine (DMT)
N,N-Dimethyltryptamine (DMT), a hallucinogenic , is a nonselective agonist for serotonin receptors including 5-HT2A.xxi DMT occurs in variety of plants species (e.g., Psychotria viridis, a shrub native to South America) across the world and can be chemically synthesized.
Ayahuasca is a brew that typically includes P. viridis and Banisteriopsis. B. caapi is woody vine found in South America that contains monoamine oxidase-A inhibitors. This botanical hallucinogen brew has been used by South America tribes for centuries for spiritual communion and healing rituals.xxii Ayahuasca is being studied for grief therapy, major depression severe, treatment resistant depression.xxiii
Ibogaine and Noribogaine
Ibogaine, a plant-based psychoactive compound found in the roots of the African shrub iboga, has historically been used in religious, spiritual and healing rituals. In the US, it is currently designated as a Schedule 1 drug; although other countries such as Mexico offer legal ibogaine treatments, which has led to some US veterans traveling to Mexico for treatment. xxiv A prospective observational study that included 30 subjects, performed by researchers at Stanford, concluded that subjects that received the combination of magnesium and ibogaine reported improvements in disability evaluated using the World Health Organization Disability Assessment Schedule and suggested an improvement in psychiatric symptoms. Substance use disorders and reduction in opioid withdraw symptoms are other conditions where ibogaine has been evaluated. xxv,xxvi
Noribogaine, a primary active metabolite of ibogaine, is being studied in substance abuse disorders and alcohol use disorders. Both ibogaine and noribogaine have shown reductions in self-administration of opioids, cocaine, nicotine, and alcohol.xxvii Noribogaine has also been studied in clinical trials for severe addiction.xxviii
The Executive Order specially called out to improve access to ibogaine under the Right To Try Act. This order may provide more avenues for the study of ibogaine and lend support for a potential new drug application for ibogaine.
Lysergic acid diethylamide LSD
Lysergic acid diethylamide (LSD) was first synthesized in 1938. Sandoz marketed Delysid (LSD) from 1947-1965 as treatment for a range of mental illness.xxix LSD can cause visual changes and extreme changes in mood, resulting in impaired depth and time perception, along with distorted perception of sensory details.xxx
LSD is currently being studied in areas such as generalized anxiety disorder and major depressive disorder. In a study of subjects with moderate to severe generalized anxiety disorder, there was dose-dependent reduction in anxiety after one dose.xxxi Earlier this year, a first patient was dosed in the second Phase 3 pivotal study in major depressive disorder, with topline results expected in 2027.xxxii In 2026, it was reported that Phase 3 readouts will come in 2026 for topline data for major depressive disorder (late second quarter) and first readout for severe generalized anxiety disorder in early third quarter of 2026.xxxiii
Risk Management for the Psychedelics
The Spravato REMS may serve as reference point for risk mitigation of psychedelics; however, new product approvals may have different pharmacokinetics and pharmacodynamics that require an individualized approach to risk management. The FDA presentation at the 2024 Advisory Committee on midomafetamine also provides insight on FDA thinking regarding the risk management for midomafetamine.
Collectively this group of drugs known as psychedelics will present with unique risk mitigation strategies when compared to selective serotonin reuptake inhibitors (SSRIs). Psychedelics can alter the patient’s mood and perception, cause hallucinations, lead to impaired judgement, and induce anxiety or panic in patients. These experiences may lead to psychological harm or irrational actions by the patient that can result in physical harm. Although pharmacokinetics and pharmacological effects and patient experiences may differ, there is likely to be overlap between the risk mitigation strategies for these products.
In general, it is anticipated that patients will need to be monitored and supported for a minimum timeframe or longer while they experience the acute effects of a psychedelic. If the FDA determines a REMS is necessary to ensure patients are monitored during the acute effects of the drug, healthcare settings will need to dedicate resources to ensure that monitoring occurs, staff are trained and available to perform monitoring. Translating the risk mitigation strategies that were performed in the clinical trials into routine practice settings could be resource intensive for many healthcare settings and create barriers that prohibit some healthcare settings from providing approved treatments. Ideally it should be a balance that ensures that each healthcare setting can provide the necessary risk mitigation without creating unreasonable burden that has a detrimental impact on patient access. The FDA’s Guidance for Industry, REMS Logic Model: A Framework to Link Program Design with Assessment provides a framework for the design, implementation and evaluation of a REMS.xxxiv This model uses a structured approach to identify evidence, assumptions, and uncertainties about risk and risk mitigation measures. Identifying the readiness of healthcare settings and potential barriers in advance and possible solutions may help with implementation and ensure that the risk management strategies are effective and implemented with fidelity. Clinical study sites or early adopters may serve as a resource for other healthcare settings that are trying to implement required risk mitigation strategies. Over time, as the drug(s) becomes integrated into the treatment of mental health, healthcare settings should be able to adapt and expand to include other drug entities that have similar risk management strategies.
Despite similarities between products and risk mitigation, there may be safety concerns that require tailoring the risk mitigation strategy to the specific drug moiety.
Counseling patients on what they may experience, how long the experience will last and a discussion of the necessary safety measures provides an opportunity for patients to ask questions, be involved in the decision-making process, and may help establish expectations.
Potential Impact of Approval of New Treatments on Non-prescription and Nonmedical Use
It is unknown what the approval of a psychedelic will have on nonmedical use or self- treatment. It is unlikely that the approval and rescheduling of these products will result in the over prescribing that occurred with opioids; however, approval and rescheduling these drugs or even initial prescribed treatment, could encourage some individuals to seek these drugs through nonprescription channels to explore nonmedical use and self-treatment. Use outside of medical settings could have a negative impact on medical use if appropriate safety measures are not taken.
Consider that Oregon, Colorado and New Mexico are 3 states that allow the use of psilocybin.xxxv, xxxvi,xxxvii The Oregon statute establishes a licensing and regulatory framework for psilocybin services in Oregon. Administration sessions can only take place at a licensed service center and manufacturing psilocybin is subject to regulation by the Oregon Health Authority. To become a licensed psilocybin facilitator in Oregon, you need to be 21 years, have a High School diploma, pass a criminal background check, complete the Oregon psilocybin services training and pass the exam and pay a fee. It is unknown what the impact these state programs may have on a REMS for an approved psilocybin or other psychedelics. The perspective piece published in New England Journal of medicine on June 13, 2026, highlights the inconsistent regulatory oversight in the US of psychedelics.xxxviii These inconsistencies are likely to create confusion for healthcare providers and patients on the expectations for treatment and ensuring safety.
With many states decriminalizing the use of psychedelics and increased public awareness about their potential therapeutic efficacy, it’s not surprising that the level of use in the general population will likely increase.
Modified Psychedelics: The potential future gamechanger for risk management of psychedelics
As psychedelics gain ground in their potential to become legal treatments for mental health conditions, a push for next generation products is already being evaluated. These modified psychedelics aim to deliver the benefits of classic psychedelics, without hallucinations. If successful, these products would remove certain barriers and concerns, such as lengthy monitoring and potential psychological distress resulting from treatment in already vulnerable patients.
Summary
The mental health community and patients are excited about the possibilities that psychedelic drugs hold for the treatment of mental health conditions, in particular treatment resistant conditions. While the evidence is encouraging, at this time ketamine and esketamine are the only psychedelic drugs that are FDA approved and only esketamine is approved for mental health conditions. As mentioned earlier, psychedelics include many different drugs, which may have unique safety profiles. Risk management for this class of drugs will evolve as more data become available about the severity of the risks, the time to onset, resolution of the acute psychedelic effects and latent effects, as well as better understanding of patient factors that may enhance or reduce the risks with these drugs.
The development of clinical guidelines and clinical practice standards will also aid in ensuring that psychedelics are safely integrated into clinical practice.
About UBC
United BioSource LLC (UBC) is the leading provider of evidence development solutions with expertise in uniting evidence and access. UBC helps biopharma mitigate risk, address product hurdles, and demonstrate safety, efficacy, and value under real-world conditions. UBC leads the market in providing integrated, comprehensive clinical, safety, and commercialization services and is uniquely positioned to seamlessly integrate best-in-class services throughout the lifecycle of a product.
About the Authors
Rachel Bonfanti, Executive Director, Risk Management & Scientific Consulting
Rachel Bonfanti, MPH, is an Executive Director, Risk Management & Scientific Consulting. In this role, she collaborates with UBC safety scientists and operational teams to develop risk management strategies. She is responsible for the creation of additional risk minimization measures (aRMM), REMS, REMS Supporting Documents, REMS tools, and REMS Assessment Reports for both single product and shared system REMS. She supports sponsors in the preparation for and participation in FDA Advisory Committee meetings and other regulatory meetings, supports REMS negotiations, and drafts regulatory communications regarding risk management topics.
Cynthia LaCivita, Risk Evaluation and Mitigation Strategy Consultant
Cynthia LaCivita, PharmD is a Risk Evaluation and Mitigation Strategy (REMS) Consultant. She formerly worked for the FDA and was the Division Director for the Division of Risk Management, in the Office of Surveillance and Epidemiology in the Center for Drug Evaluation and Research. While at the Agency, she has worked on the development and evaluation of numerous REMS and REMS modifications.
