Interest in psychedelic treatments for Depression has increased dramatically in recent years. Psilocybin, LSD, DMT, and related compounds are being studied for a range of psychiatric conditions, with treatment-resistant Depression (TRD) among the most important targets.
A 2026 review in Neuropsychopharmacology by Philip D. Harvey and Charles B. Nemeroff examines the field of psychedelic psychiatry, including the evidence for psychedelics in Major Depressive Disorder (MDD) and TRD. The authors describe enormous interest, with hundreds of studies underway, and several promising findings. They also state plainly that there are currently no approved psychedelic treatments for any psychiatric condition, and they raise important questions about safety, durability, study design, accessibility, and how these treatments would fit into routine psychiatric care.
For patients with difficult-to-treat Depression, these developments are important. At the same time, it is useful to distinguish treatments that are available in clinical practice from treatments that remain investigational.
What Is Treatment-Resistant Depression?
TRD generally refers to MDD that has not responded adequately to appropriate antidepressant treatment. The exact definition varies between studies, and the review notes that diagnostic systems do not formally define TRD, so each trial sponsor must reach agreement with regulators on its own definition. Many clinical frameworks consider failure to improve after two appropriate antidepressant trials to represent TRD.
TRD is a significant clinical problem because some patients continue to have substantial symptoms despite multiple medications. Persistent Depression can affect work, relationships, sleep, motivation, concentration, and overall quality of life.
The search for treatments that work through mechanisms different from conventional antidepressants has therefore become an important area of research. Transcranial magnetic stimulation (TMS), Spravato® (esketamine), electroconvulsive therapy (ECT), and investigational psychedelic treatments approach Depression through different biological mechanisms and treatment strategies.
Why Are Psychedelics Being Studied for Depression?
The psychedelic compounds receiving the greatest attention for Depression include psilocybin, LSD (lysergide), and several related compounds. Classical psychedelics, including psilocybin, LSD, mescaline, and DMT, act as agonists at the serotonin 2A receptor. Researchers believe this produces downstream effects that may alter brain networks involved in mood, cognition, and emotional processing. The review also notes the suggestion that psychedelics induce neuroplasticity, although the time course and extent of that effect are not well defined, and its relationship to lasting clinical improvement remains under investigation.
One feature that sets psychedelic treatment apart is that some trials use a single dose, or a single day of dosing, rather than the repeated daily dosing typical of antidepressant medication. That creates an intriguing possibility: could a small number of treatment sessions produce an antidepressant effect that lasts for weeks or months? The answer is not yet fully established. If the effect is time-limited, redosing strategies will be needed, and a meta-analysis cited in the review suggested that multiple doses of psilocybin produced more sustained benefit for Depression than a single dose.
Psilocybin and Treatment-Resistant Depression
The review identifies MDD and TRD as the most common targets for psychedelic research. One of the most important areas involves psilocybin given with structured psychological support, and the review names Phase 3 programs of psilocybin for TRD and of deuterated psilocybin for MDD among the most advanced.
The TRD program follows an earlier randomized study in which patients received a single 1 mg, 10 mg, or 25 mg dose of psilocybin. Over a 12-month follow-up, the 25 mg dose was associated with greater sustained benefit than the 1 mg and 10 mg doses. A separate Phase 2 study described in the review compared a single 25 mg dose of psilocybin with a 100 mg niacin comparator, both combined with supportive treatment. Depression and self-reported functioning were better with psilocybin at 43 days, and adverse events were more common with psilocybin. That study did not assess functional unblinding, although clinical ratings were made by remote raters.
These findings have generated considerable interest because TRD is precisely the population in which conventional approaches become increasingly difficult. The authors also point out that psychedelic-assisted treatment requires a substantial investment of time and effort, which affects cost and access. Payers commonly cap coverage for psychotherapy sessions, and some current treatment models include more therapy visits than payers are willing to cover.
Phase 3 Results for Psilocybin: Encouraging, but Interpret Carefully
The review discusses top-line results, announced in a company press release, from the first Phase 3 study of psilocybin-assisted treatment for TRD. Active treatment combined with psychological support improved scores on the Montgomery-Ã…sberg Depression Rating Scale (MADRS) by 3.6 points more than placebo combined with psychological support, a statistically significant difference. There was no difference between groups in suicidal ideation. The authors noted that full results were still pending when they wrote the review, and that the clinical significance of the difference must be weighed against the severity of illness in the participants and the substantial time and effort the treatment requires. They also noted that the cost-benefit of this treatment will need to be evaluated.
Since the review was written, the sponsor, Compass Pathways, has announced further results. In February 2026, the company reported that its second Phase 3 trial (COMP006) met its primary endpoint at week 6, and in July 2026 it announced 26-week results from that trial, which enrolled nearly 600 participants. Trade press reported that 39% of participants in the 25 mg arm reached a clinically meaningful response, defined as at least a 25% reduction in MADRS score at week 6 after two doses, a lower bar than the 50% reduction conventionally used to define response. The company says it expects to complete a rolling New Drug Application to the FDA in the fourth quarter of 2026 and anticipates a launch in the first half of 2027, subject to FDA approval and Drug Enforcement Administration rescheduling.
These are sponsor-reported results. Detailed data and the FDA’s independent review will allow a closer assessment of how large and how lasting the benefit is.
Other Compounds in Development: LSD, DMT, and MDMA
Although psilocybin has received much of the public attention, it is only one of several compounds being investigated. A tracker cited in the review, updated in early 2025, counted 14 Phase 2 trials of psilocybin alone, 12 trials of other psychedelics, and 24 Phase 1 trials across psychiatric conditions. For Depression, the pipeline includes LSD-related compounds, DMT, MDMA, and other experimental treatments.
MM120: An LSD-Derived Treatment Being Studied for Major Depression
One of the most significant developments involves lysergide D-tartrate, known as MM120, an investigational formulation of LSD developed by Mind Medicine in a rapidly dissolving oral tablet. (The developer has since been renamed Definium Therapeutics and designates the compound DT120; we use MM120 here to match the review.) MM120 is notable because it has reached Phase 3 testing for MDD.
According to the review, the first Phase 3 MDD study, called Emerge, launched on April 15, 2025 as a 52-week program in two parts. Part A is a 12-week, randomized, double-blind, placebo-controlled trial of a single 100-microgram dose of MM120 versus placebo, with participants randomized 1:1. The primary outcome is the change in MADRS score at six weeks, a clinician-rated measure commonly used in Depression trials. Part B is a 40-week extension during which participants may receive open-label MM120 depending on symptom severity. The design illustrates a central question facing the field: can a single treatment produce an antidepressant effect that lasts, and if symptoms return, can retreatment restore the benefit? The review notes that the extension studies plan redosing at intervals determined by clinical need.
In June 2026, the sponsor announced positive topline results from Part A of Emerge, which enrolled 149 adults with MDD (not specifically treatment-resistant Depression). The company reported that participants receiving MM120 improved by 8.1 more MADRS points than those receiving placebo at week 6, that the difference was 14.2 points at week 1 and about 7 points at week 12, and that remission at week 6 was 24% with MM120 compared with 3% with placebo. These are topline results from a single trial, announced by the sponsor. A second MDD study, Ascend, adds a lower-dose 50-microgram arm in an effort to address concerns about functional unblinding, with results expected in 2027.
Why Study Design Matters in Psychedelic Trials
The MM120 studies are noteworthy for the care taken in how Depression outcomes are rated, including remote raters and extensive training and supervision for in-person raters. This matters because Depression trials can be influenced by differences in how symptoms are assessed.
It is especially relevant in psychedelic research because blinding is difficult to maintain. Participants receiving an active psychedelic often recognize it from the subjective effects, and the review notes that most participants in psilocybin and MDMA trials correctly identified their treatment. Awareness of assignment can exaggerate perceived benefit and can produce negative (nocebo) responses in people who realize they received placebo. Researchers therefore have to consider how much of an observed improvement comes from the drug itself, from expectations, from psychological effects, or from some combination. Proposed solutions include active placebos, dose-response designs, very low “microdose” comparators, and comparisons with existing treatments, but it is not yet clear which of these approaches regulators will accept as an adequate control.
The results of these Phase 3 programs will therefore matter not only for individual compounds but for the broader question of whether psychedelic-based treatments can move from promising early research to widely accepted treatments for Depression.
DMT
DMT (N,N-dimethyltryptamine) is a classical psychedelic that acts mainly at serotonin 2A receptors. DMT and the related compound 5-MeO-DMT have a very rapid onset and offset: when inhaled or given intravenously, effects begin almost immediately and may last only 15 to 30 minutes, compared with roughly 4 to 6 hours for oral psilocybin or LSD. That could shorten treatment sessions and change the cost and practicality of treatment.
This raises a central scientific question: does the antidepressant benefit require a prolonged psychedelic experience, or can changes in brain function and neuroplasticity produce a therapeutic effect even when the altered state is brief? The review describes this as a major unresolved controversy. Some researchers argue that benefit tracks the intensity of the experience. In a small open-label study of 12 people with severe TRD treated with psilocybin, for example, the intensity of a feeling of “oceanic boundlessness” correlated with the degree of antidepressant response. Others are not convinced, and compounds designed to promote plasticity without a psychedelic experience are in development, although the review notes they are years behind existing compounds. Clinical trials are needed to answer the question.
LSD
LSD is also being studied in modern clinical trials, separate from the development of MM120. LSD was investigated in psychiatry decades ago, and current research is revisiting the compound with contemporary trial methods, standardized dosing, and more rigorous outcome measurement. We recently reviewed two 2025 LSD-related trials in more detail in a separate post.
The renewed investigation of LSD shows that the current field is not simply a resurgence of interest in psilocybin. Researchers are examining whether different psychedelics have different therapeutic profiles, durations of action, and safety considerations. The goal is not necessarily to establish one psychedelic as universally effective, but to determine which compounds may help which conditions or patients.
MDMA
MDMA’s proposed therapeutic applications have focused more on post-traumatic stress disorder than on Depression, although the review lists MDMA among the compounds in Phase 2 studies for MDD and TRD. MDMA is pharmacologically different from classical psychedelics. Its mechanism is not directly serotonergic but stimulant-like, its effects are not blocked by a serotonin 2A antagonist, and in comparison studies its subjective effects resembled amphetamine more than LSD. It produces a state of positive mood and sociability rather than the visual and perceptual changes typical of classical psychedelics. This is one reason the term “psychedelic” is increasingly used as an umbrella for compounds with very different effects.
MDMA is also the cautionary example in the review. The most advanced MDMA program, for PTSD, included two Phase 3 studies of 90 and 104 participants that reported positive results, yet an FDA advisory panel turned the application down in June 2024 and the agency disapproved it. Concerns raised included functional unblinding, therapist misconduct, prior psychedelic exposure among many participants, and a lack of validation of the therapy delivered alongside the drug. The review’s authors note that these concerns could apply to trials of classical psychedelics as well.
The Pipeline Is Large, but No Psychedelic Treatment Is Approved
The review states that there are no approved psychedelic treatments for any psychiatric condition. The FDA has granted Breakthrough Therapy designation for several targets, including MDMA for PTSD, LSD for generalized anxiety disorder, and psilocybin for TRD, a status intended to speed development rather than a form of approval.
A compound entering Phase 2 or Phase 3 development is not the same thing as a treatment that has demonstrated sufficient evidence for routine clinical use and received regulatory approval for a particular indication. Phase 2 studies generally provide preliminary information about efficacy, dosing, and safety. Phase 3 trials are designed to provide larger-scale evidence and are part of the process of determining whether a treatment can become an approved therapy.
As the review points out, psychiatry has historically struggled to move treatments successfully from Phase 2 into Phase 3, and promising early findings do not always translate into successful confirmatory trials. That several sponsors have now reported positive Phase 3 results is a meaningful step, but these are company announcements, and FDA review will be the next test.
Safety: What We Know So Far
The review emphasizes that investigational products given in supervised trials differ substantially from illicitly obtained psychedelics, which may be combined with other substances or contain adulterants. Data from supervised trials suggest the safety risks, both acute and long-term, are lower than those of illicit use. Legitimate concerns remain, however. Many studies have had limited safety assessments and limited long-term follow-up. Psychedelics increase blood pressure, which raises the risk of stroke in people with pre-existing hypertension. Serious cardiac events appear rare but can occur in a small number of people with identifiable risk factors. Serotonin-related conditions are a possible risk. Hallucinogen persisting perception disorder (HPPD), a syndrome of persistent perceptual disturbances reported in some people with regular psychedelic use, is not well understood and will need close monitoring, although cases appear few relative to the number of people exposed.
Special populations require particular attention. The safety of psychedelics in people with a history of psychosis or bipolar disorder needs careful evaluation, and older adults are underrepresented in research: fewer than 2% of participants in earlier psilocybin trials were over 65, even though TRD is common in older adults. The review also notes that approval of a psychedelic treatment would place psychiatrists in more of a gatekeeping role because of abuse potential.
What Could We Learn From These Studies?
The new research may answer several fundamental questions about Depression treatment. First, can a single treatment produce sustained antidepressant benefit? Second, which patients are most likely to respond? Third, does the intensity of the psychedelic experience contribute to the antidepressant effect? Fourth, how often would treatment need to be repeated? And finally, can these treatments be delivered safely and practically at scale?
These questions are especially important for TRD. A treatment that requires only one or a few sessions could represent a very different model from daily antidepressant medication. At the same time, psychedelic-assisted treatment may require substantial preparation, supervision, and follow-up, so the overall treatment experience, not only the compound, will need to be evaluated. The review also notes that studies to date have rarely separated the effect of the drug from the effect of the accompanying psychotherapy, which may matter for both regulators and insurers.
Where Does This Leave Patients With Treatment-Resistant Depression Today?
The research is an exciting development in psychiatric drug development. Psilocybin, LSD-derived compounds such as MM120, DMT, and other compounds are being studied in clinical trials, and several sponsors have now reported positive late-stage results. But for patients living with TRD today, it is important to distinguish what is being studied from what is available. As of this writing, no psychedelic treatment is FDA-approved for Depression or any other psychiatric condition.
At Mid City TMS, patients with difficult-to-treat Depression can discuss established options, including TMS and Spravato, with Dr. Bryan Bruno, Medical Director. The development of psychedelic treatments does not make these options less relevant. It highlights the widening range of biological approaches being studied for Depression.
How Does This Compare With TMS and Spravato?
TMS uses magnetic pulses to stimulate specific brain regions involved in mood regulation. It does not require anesthesia and does not involve an altered state of consciousness. TMS is an established, noninvasive treatment option for Depression, including TRD.
Spravato is another established option for appropriate patients with TRD. Unlike classical psychedelics, esketamine acts mainly through the glutamate system rather than the serotonin 2A receptor, and the review distinguishes esketamine from the classical psychedelics and notes that it is already FDA-approved for TRD. The review also notes that a subset of people receiving ketamine or esketamine experience psychedelic-like perceptual effects, which is one reason Spravato is given with monitoring; at our office, patients stay for observation after each session.
The growing interest in psychedelics does not mean that patients with TRD need to wait. There are already evidence-based treatment options that can be considered now.
Why Treatment Should Be Individualized
TRD is not a single biological condition. Patients arrive at TRD through very different treatment histories and can have different symptoms, medical conditions, treatment preferences, and previous responses. The most appropriate treatment may therefore differ from one patient to another.
At Mid City TMS, we believe treatment decisions should be based on an individualized discussion of the available options. Depending on the patient’s circumstances, that discussion may include medication strategies, TMS, Spravato, and other appropriate psychiatric treatments. As psychedelic research advances, this individualized approach matters even more: a treatment that may eventually be appropriate for one patient may not be appropriate for another.
If you or a loved one has Depression that has not responded to medication, learn how Mid City TMS can help and contact us today to schedule a consultation about the options available now.
Sources
Harvey PD, Nemeroff CB. Psychedelic therapeutics in psychiatric conditions. Neuropsychopharmacology. 2026.