Psychedelic research timeline
Major Depressive Disorder (MDD): the psychedelic research timeline
MDD is where several psychedelic development programmes meet the much larger ketamine and esketamine record. This timeline keeps the focus on the trials that changed the clinical argument rather than repeating every depression study.
Milestones are editorially selected from Blossom’s research catalogue. Future markers are limited to important trials with dated public guidance and are shown as planned, not promised.
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The rapid-antidepressant question
1997 to 2014Ketamine changes the expected speed of response.1997-01
Yale University
Berman’s Yale crossover trial
Seven patients, a saline placebo, and depression scores falling within hours rather than weeks.
A tiny randomised, double-blind, placebo-controlled crossover pilot at Yale. Seven patients. Published in Biological Psychiatry in February 2000, it is now the most-cited paper in Blossom’s entire ketamine set at over 3,800 citations.
What made it startling was speed. Conventional antidepressants take four to six weeks to separate from placebo, and the field had largely accepted that as a property of how depression lifts. Ketamine moved scores within hours, which implied the delay was a property of the drugs, not the illness.
Hold two things at once here. This result reoriented an entire subfield and remains the origin point for everything below it on this canvas. It was also seven people in a crossover design, and a single small trial is a hypothesis rather than a finding. It took six more years for anyone to replicate it properly.
2004-07
National Institute of Mental Health (NIMH)
NIMH opens the replication programme
Carlos Zarate’s intramural study runs for thirteen years and produces the trial that made the field believe.
The National Institute of Mental Health put its intramural programme behind replicating Berman, and the 2006 readout is the moment the antidepressant claim stopped being a curiosity. Government money, not industry money, did that work.
The registry record runs to 2017, which tells you something about how these programmes actually operate. It is a long-running platform study rather than a single readout, and the famous result comes from an early slice of it.
The economics here are worth stating plainly. Ketamine was already generic in 2004, so no company had a patent worth defending and no company was going to fund the pivotal work. Public funding filled the gap. When you reach the esketamine thread below, notice that the compound which attracted commercial development was the one that could be patented.
2012-01
University of São Paulo, Ribeirão Preto
The first clinical trial opens in Brazil
An open-label study gives a single dose of church-prepared ayahuasca to patients with recurrent depression, with SPECT imaging before and after.
The formal clinical record starts here, 161 years after the first European note and roughly two decades after the Hoasca Project. It is a small, unregistered, single-arm study: seventeen patients, one dose, symptom scales out to three weeks, and brain perfusion imaging to see whether anything changed physically.
Depression scores fell quickly and stayed down over the follow-up, and perfusion increased in regions associated with emotional processing and interoception. In an open-label design with no control group, none of that separates drug effect from expectation, and the authors said so. What the study established was feasibility: that this could be done at all, in a hospital, with a preparation obtained from a church and its alkaloid content verified.
The preliminary report appeared in 2015 and the imaging paper in 2016. Both are among the most cited ayahuasca papers in Blossom, which is itself a comment on how thin the interventional literature is.
2014-02
Federal University of Rio Grande do Norte
The randomised placebo-controlled trial
A trial in Natal randomises patients with treatment-resistant depression to a single dose of ayahuasca or an inert placebo, with response measured to seven days.
This is the study the rest of the canvas points at. Randomised, parallel-group, with a placebo built to match the taste and colour of the brew, in patients who had already failed at least two antidepressants. Depression scores were significantly lower in the ayahuasca group at one, two and seven days, and the effect was large enough to show up in a sample this size.
Three limitations belong next to that result and are stated in the paper. The sample is small, so the confidence intervals are wide. The follow-up is seven days, which says nothing about durability. And blinding almost certainly failed, because a substance that produces vivid visual imagery and vomiting is not hard to distinguish from mineral water; the placebo arm improved substantially too, which tells you the comparison was not psychologically inert.
It has been cited more than eight hundred times and it remains, a decade later, the only adequately powered randomised placebo-controlled ayahuasca trial for a psychiatric indication in this database. Compare the compounds that have a pharmaceutical sponsor: psilocybin went from a first randomised readout to multi-site Phase 3 in under a decade. Ayahuasca produced a positive randomised result in 2018 and nothing has been built on it, because there is nobody whose job it is to build on it.
Psychedelics enter MDD
2015 to 2023Open-label signals become comparative and randomised trials.2015-01
Imperial College London
Imperial opens the depression question
An open-label feasibility study in treatment-resistant depression at Imperial College London.
Robin Carhart-Harris and colleagues run a small open-label study in patients whose depression had not responded to existing treatment. No control arm, no blinding, twelve patients. The results, published in Lancet Psychiatry in 2016, showed large symptom reductions that persisted at six months in some participants.
Open-label results in depression should always be read carefully, because expectation alone moves depression scores and these participants knew exactly what they had taken. The study was designed to establish feasibility, and it did. What it also did was give every commercial programme further down this canvas a number to point at when raising money.
2019-03
Janssen Pharmaceuticals
FDA approves Spravato
Esketamine nasal spray is cleared for treatment-resistant depression, the first genuinely new antidepressant mechanism in decades, under a restricted distribution programme.
Janssen took the S-enantiomer, delivered it intranasally, and got the patent protection that racemic ketamine could never offer. That is the whole commercial logic of the programme, and it worked. Thirty-two years after fluoxetine, psychiatry had an approved antidepressant that did not act on monoamines.
Approval came with a REMS, a risk evaluation and mitigation strategy: administration in a certified clinic, direct observation while the dose is taken, two hours of monitoring afterwards, and no take-home supply. Those conditions exist because of the dissociation, the sedation and the blood-pressure rise, and they are defensible on safety grounds.
They are also the product’s central commercial problem. Two hours of monitored clinic time per dose, twice a week during induction, is expensive to staff and awkward to schedule, and the reimbursement often does not cover the chair time. Several later markers on this canvas exist because somebody is trying to get rid of that requirement.
The uncomfortable framing, which deserves to be stated rather than hinted at: this is a patented enantiomer of a cheap generic that any licensed prescriber could already use off-label. That is a commercial strategy as much as a pharmacological one. The fair counter is that nobody else was going to fund a 1,500-patient registration programme for a compound with no exclusivity, and without one there would be no approved, quality-controlled, labelled product at all. Both things are true.
2019-11
GH Research
Phase I/II in depression
The first patient study of GH001, running nearly two years through the pandemic.
The first time the compound is given to patients rather than healthy volunteers, which is the step where a programme starts generating evidence about benefit rather than safety alone.
The near-two-year run reflects pandemic recruitment conditions as much as protocol design. Read trial durations on this canvas with that caveat: the bars measure elapsed time, not effort or difficulty, and 2020 stretched almost everything.
2021-04
Small Pharma Ltd
The commercial thesis enters the clinic
Small Pharma opens a Phase 1/2a of SPL026, an intravenous DMT fumarate, in healthy volunteers and patients with major depressive disorder.
Here is the argument the whole commercial lane rests on. A psilocybin session occupies six to eight hours, two therapists and a dedicated room, and that cost is the reason psychedelic therapy is hard to fit into a health system. An intravenous DMT session lasts minutes. If the antidepressant effect survives the compression, the economics change completely.
SPL026 was the first serious test of that proposition. Small Pharma ran it as an integrated programme rather than a single study: healthy-volunteer safety first, then patients, then a follow-on asking whether the effect survives concurrent SSRI treatment, which matters enormously because most people with depression who would be offered this are already taking one.
The proposition remains unproven, and it is worth naming what could break it. Antidepressant response to psychedelics may depend on the duration of the experience rather than merely on its occurrence. A shorter session leaves less room for the psychological work that most protocols treat as the active ingredient. Nobody has yet run the head-to-head study that would settle it.
2021-04
New England Journal of Medicine
Psilocybin fails to beat escitalopram on the primary endpoint
The first head-to-head against a standard antidepressant publishes in the New England Journal of Medicine. The primary endpoint is not met.
Imperial College London runs psilocybin directly against escitalopram, a widely prescribed SSRI, in moderate-to-severe depression. On the primary endpoint, the difference between the two is not statistically significant. Several secondary measures favoured psilocybin, and the trial was not powered for the comparison it is most often quoted for.
This trial is routinely reported as a psilocybin win and routinely reported as a psilocybin failure, depending on who is doing the reporting. Both readings are selective. The honest summary is that a 59-participant study could not distinguish the two treatments on its pre-specified measure, which is a real result and a genuinely underpowered one.
A six-month observational follow-up published in 2024 found the groups had converged further. Head-to-head comparisons against active treatment are the hardest test a new psychiatric drug can face, and this remains the only one psilocybin has attempted.
2022-06
Neuropsychopharmacology
First depression data reach print
An exploratory report covers dose-related safety, tolerability and efficacy of intravenous DMT in healthy volunteers and in major depressive disorder.
This is the paper that made the short-duration case look plausible rather than merely clever. It reports dose-related safety and tolerability alongside an efficacy signal in patients, which is what a Phase 1/2a is supposed to produce and what most compounds at this stage fail to.
Exploratory is the operative word. Small samples, open questions about blinding, and an efficacy read that was never powered to be definitive. In psychedelic research the gap between a promising early signal and a controlled replication has repeatedly turned out to be wide, and treating an exploratory readout as proof of concept is how the field keeps disappointing itself.
A companion pharmacokinetic paper published the same year characterised how DMT fumarate behaves in the body, and a 2023 modelling study went on to derive infusion rates that hold the experience at a target intensity. That kind of work is unglamorous and it is what turns a drug into a dosing protocol.
2023-09
JAMA
Usona Phase 2 publishes in JAMA
A single 25 mg dose beat an active placebo over six weeks in 104 participants with major depression.
Usona’s PSIL201 study reports a rapid and sustained antidepressant effect against a niacin active placebo, in the general major-depression population rather than the treatment-resistant one. It is the strongest evidence supporting the Phase 3 that follows six months later.
The trial has an awkward companion record. Its long-term follow-up study was terminated in October 2022, which means the durability question the original trial raised was not answered by the study designed to answer it. Terminations rarely come with an explanation, and this one does not.
2023-10
Nature Mental Health
ended earlyKetamine masked by surgical anaesthesia: no difference
Given to patients already unconscious for surgery, so nobody could tell who received it, ketamine did not beat placebo.
The cleverest trial design on this canvas, and the most uncomfortable result. Patients undergoing surgery were randomised to ketamine or placebo while already under general anaesthesia, which makes the blind genuinely airtight. Neither patients nor raters could tell.
Both groups improved substantially. Neither improved more than the other.
One interpretation is that a meaningful part of ketamine’s antidepressant effect in ordinary trials comes from expectation, made powerful by the unmistakable experience of having received something. Another is that a patient who is unconscious cannot have the experience that does the therapeutic work. A third is that the trial was small, in a surgical population, and does not generalise.
Nobody knows which is right, and a 2026 systematic review of blinding integrity across psychedelic trials suggests the problem is not confined to ketamine. This is the strongest existing challenge to the whole edifice above it, so it belongs here at full weight rather than in a footnote.
Several pivotal bets
2024 onwardsLSD, psilocybin analogues and short-acting tryptamines move towards larger tests.2025-04
Definium Therapeutics
Phase 3 opens in major depression
Emerge takes the same formulation into a second and much larger indication.
Depression is a far bigger market than generalised anxiety and a far more crowded one, with two decades of failed novel mechanisms behind it. Opening a second pivotal indication before the first has read out spreads the risk and raises the stake at the same time.
A second MDD study, Ascend, began in May 2026 and runs to mid-2028.
2025-04
Neuropsychopharmacology
Vaporised DMT reports an antidepressant signal
A Phase 2a in treatment-resistant depression reports rapid and sustained antidepressant effects from vaporised DMT, the first efficacy readout for the compound itself.
Five years after the first registered trial, DMT has an efficacy result. It is Phase 2a, so it is small and exploratory, and it reports both rapid onset and effects that persist beyond the day of dosing, which is the pattern the whole field is looking for and rarely finds in a single study.
Treatment-resistant depression is a demanding population and a forgiving one at the same time. Demanding, because these patients have already failed several adequate trials of standard treatment. Forgiving, because expectancy runs high in people who have exhausted the alternatives and know they are receiving something novel, and an unblinded psychedelic maximises that.
A companion randomised double-blind study of vaporised DMT published two months later gives the safety and subjective-effects picture from a controlled design. Read together, the two make a reasonable case for proceeding, and no case at all for concluding.
2025-09
University of Basel
Basel depression trial: a near miss
61 patients, high dose against low dose. The clinician-rated difference was significant until baseline severity was accounted for, and then it was not.
The honest reading of this result is that it is inconclusive. Self-rated depression scores favoured the high dose but missed significance (p = 0.059). Clinician-rated scores reached significance (p = 0.023) and then lost it once baseline severity was adjusted for (p = 0.086).
The authors called for a larger Phase 3, which is the correct conclusion and also the one that keeps a programme alive. It is worth naming what this study cannot tell us: with 61 patients and a low-dose comparator rather than placebo, it was never going to settle the question.
It sits directly below the MM120 depression programme on this canvas, which is running two pivotal trials on a related premise with far more money behind it and no published depression result of its own.
2026-03
JAMA Psychiatry
GH001 randomised trial in JAMA Psychiatry
GH001 beats placebo in a randomised controlled trial, the strongest evidence on this canvas.
The first randomised, placebo-controlled evidence for any 5-MeO-DMT compound, published in JAMA Psychiatry in March 2026. Randomisation and a placebo arm are what separate a suggestive result from a credible one, and until this point every study on this canvas lacked both.
It belongs to GH Research, not to the programme Lilly acquired. Read the two clinical lanes together and an awkward pattern appears: the sponsor with the stronger published evidence is not the sponsor that got bought.
One caution before treating this as settled. A single randomised trial is a beginning, not a conclusion, and independent replication is what turns it into an approvable claim.
2026-10
Helus Pharma
plannedAPPROACH topline expected
Company guidance puts the first pivotal readout for HLP003 in the fourth quarter of 2026.
The nearest thing to a verdict on this canvas. APPROACH is the first of the two PARADIGM pivotal studies, and Helus guides to topline data in the fourth quarter of 2026. This is company guidance rather than a registry-confirmed date, so treat it as the optimistic case.
What a positive result would and would not establish is worth being clear about now, before the headlines arrive. It would show a deuterated psilocin analogue, given alongside an existing antidepressant, outperforming a low-dose comparator in major depression. It would not show that psilocybin is an approved medicine, and it would not resolve the blinding question that has shadowed every trial above it.
A negative result would be more consequential. Two decades of accumulated signal, and the field’s first properly powered pivotal test, would have failed to converge.
Major Depressive Disorder (MDD)
The modern psychedelic and rapid-acting antidepressant story in MDD
Research Landscape
What the registered trials connected to Major Depressive Disorder (MDD) look like when you line them up. Counts come from Blossom’s trial records as of August 2026.
How fast is Major Depressive Disorder (MDD) research growing?
SourcedRegistered trials by recorded study-start year; 27 earlier trials began before 2013. Click a year for the running total.
Don't read as total research effort: only registered trials with a recorded start date are counted (319 of 319 tracked). Recent years under-count because of registration lag; striped bars are still filling in or are planned starts.
What's live right now, and what stopped?
SourcedRegistry status of all 319 Major Depressive Disorder (MDD) trials Blossom tracks. Orange marks trials recruiting or opening.
- Recruiting or opening
- 8025%
- Underway, not recruiting
- 196%
- Completed
- 15248%
- Stopped early
- 3611%
- Unknown / other
- 3210%
Don't read stopped trials as failures: trials end early for funding, recruitment, and strategy reasons too. Status is as last synced from the registry; some 'recruiting' trials may already have finished.
Which compounds carry the Major Depressive Disorder (MDD) research?
SourcedTrials per compound. Orange marks the most-studied compound.
Don't read shares as adding to 100%: a trial testing several compounds counts once per compound, and placebo comparator arms are not shown. Trial volume signals research attention, not evidence quality.
Publication Landscape
How the 399 papers Blossom links to Major Depressive Disorder (MDD) line up by year, compound and journal. This is the psychedelic-relevant literature in Blossom's records as of August 2026, not the condition's full medical literature.
How has Major Depressive Disorder (MDD) research grown?
SourcedTracked papers by publication year; 3 earlier papers published before 2012. Click a year for the running total.
Don't read as total output: only the 399 of 399 tracked papers with a recorded publication date are counted, and these are the psychedelic-relevant papers Blossom tracks, not a complete bibliography. The current year is still filling in.
Which compounds shape Major Depressive Disorder (MDD)?
SourcedTracked papers per compound. Orange marks the largest literature.
A paper studying several compounds counts once per compound, and placebo comparator arms are not shown. These are the psychedelic-relevant papers Blossom tracks.
Where is Major Depressive Disorder (MDD) research published?
SourcedTracked papers per journal. Orange marks the most-used journal.
Counts the journal recorded on each tracked paper; papers without a journal on file are omitted. Blossom tracks psychedelic-relevant papers rather than each journal's full catalogue.