European psychedelic depression development has quietly split into two camps, and the dividing line is a single eligibility rule: whether patients have to come off their antidepressants before they can be dosed.

Start with the camp that is furthest along. Compass Pathways' COMP360 psilocybin, two positive Phase 3 pivotals and an NDA in rolling review, requires a washout. Its protocol has patients taper off antidepressants inside the first four weeks of screening, then sit at least two weeks completely unmedicated before the baseline visit, with some drug classes requiring immediate cessation and a longer clearance. Germany's EPIsoDE trial, the blinded readout we have tracked since Issue 2, did the same: taper before, stay off for weeks after. The rationale is mechanistic. SSRIs occupy and downregulate the same serotonergic receptors psilocybin acts on, so the worry is that a medicated brain dampens the drug.

Now the other camp. Cybin's CYB003, a deuterated psilocin analogue running a three-study Phase 3 program whose multinational trial is already recruiting at European sites including Greece, Ireland, Poland and the UK, is built as an adjunctive treatment: patients stay on a stable antidepressant and take CYB003 on top, no taper. And AtaiBeckley has published a study in CNS Drugs showing BPL-003, its 5-MeO-DMT nasal spray, dosed once in treatment-resistant patients who stayed on their SSRIs, with a 66.7% response rate by Day 2.

Here is why this is a commercialization fault line, not a footnote. Real-world treatment-resistant patients are, almost by definition, on antidepressants. A therapy that demands a supervised multi-week washout imports a relapse risk, a discontinuation-syndrome risk, and weeks of delay before anyone is even dosed. That shrinks the practically treatable population and complicates every reimbursement conversation before it starts. The adjunctive camp is betting that convenience wins. The washout camp is betting the molecule needs a clear receptor to work. Both cannot be right, and Europe is where the bet gets settled, because the adjunctive Phase 3 is the one already enrolling patients at EU sites.

How good is the evidence that washout actually matters? Thinner than either camp implies. The most useful data on the question comes from Compass's own program: a published analysis of 233 treatment-resistant patients comparing those who discontinued antidepressants to enter the trial against those who arrived medication-free. That is the paper to read before assuming a washout is either essential or pointless. The adjunctive case, meanwhile, is still mostly promise. BPL-003's on-SSRI result is real but tiny: a single-center, open-label, 12-patient study, six dosed at 10mg and six at 12mg, no control arm. It is exactly the design this newsletter has spent two issues distrusting, because open-label psychedelic trials flatter the drug. It shows that co-dosing with an SSRI is feasible and safe. It does not show the effect is real. The serious test of the adjunctive bet is CYB003, where the same question runs inside a placebo-controlled Phase 3 at scale.

Denmark is measuring what an LSD dose actually occupies in the brain. Rigshospitalet in Copenhagen updated its trial measuring LSD occupancy of the serotonin 2A receptor in the human brain, an early-phase PET study now active and no longer recruiting. It is the receptor-level pharmacology that sits directly under this week's lead: if you want to argue about whether an SSRI-occupied receptor blunts a psychedelic, someone first has to measure the occupancy. Copenhagen is doing that homework. (NCT05953038, updated 2 July)

France's psilocybin trial in alcohol use disorder has started enrolling. CHU Nîmes moved its study of psilocybin for relapse prevention in alcohol use disorder with depressive symptoms from not-yet-recruiting to recruiting. We flagged the registration in Issue 3; the status change means an academic-led French Phase 3 in a non-depression indication is now taking patients. (NCT07638553, updated 1 July)

12. The number of patients behind the headline that BPL-003 works alongside an antidepressant. Six were dosed at 10mg and six at 12mg, all staying on a stable SSRI, with durable responses to Week 12 (83% at 10mg, 66.7% at 12mg). What it reveals: the adjunctive camp's most-quoted new data point rests on twelve people and no control group. Plausible and commercially enormous, but as evidence it's a proof of concept, not a result. The trial that settles the adjunctive question at scale is CYB003's placebo-controlled Phase 3, now enrolling (NCT06793397). (BPL-003 Phase 2a data: NCT05660642, Part 2 of a four-part study, via AtaiBeckley, 8 April 2026.)

EU / trial authorization: Cybin's CYB003 Phase 3 (EMBRACE, NCT06793397) is recruiting at European sites including Ireland, Poland and Greece, alongside the UK, which means national regulators in multiple EU member states have cleared a psychedelic dosed on top of a standard antidepressant to enroll patients. Clinical-trial authorization, not marketing approval, but it puts the washout question on European soil, in patients, now.

EMA: Nothing psychedelic-specific surfaced. Still a blind spot, not a finding: nothing we can see, which isn't the same as nothing moving.

Germany / BfArM: The psilocybin compassionate-use pathway is still pending a primary source beyond secondary reporting. Carried from Issues 3 and 4, not yet confirmed.

Scoring the open calls. Two calls are live, and neither has resolved. Issue 3's call, that AtaiBeckley reports its first BPL-003 Phase 3 patient dosed in Q3 2026, resolves on 30 September; it remains open. Issue 4's call, that Definium's Panorama will post a smaller placebo-adjusted effect than its sister trial Voyage, resolves once both GAD toplines are public; neither has read out, so it stays open. No score to book this week, which is how an honest ledger reads when the clock has not run out.

This week's call. AtaiBeckley's BPL-003 Phase 3 program, when it registers, will use an adjunctive design that lets patients stay on a stable SSRI, rather than mandating an antidepressant washout. In plain terms: BPL-003 commits to the adjunctive camp. The tell is that the company built and published a dedicated on-SSRI study; you do not assemble that evidence base only to force a washout in your pivotal. Falsifiable and checkable: when the BPL-003 Phase 3 protocol posts to ClinicalTrials.gov, expected in H2 2026, its eligibility criteria will not require patients to discontinue a stable SSRI before dosing. If the Phase 3 mandates a washout, I am wrong. Resolve: on the BPL-003 Phase 3 registry posting.

If something here is wrong, tell me, and I will correct it openly.

Thank you so much for reading.

Dhruv

Sources

Compass COMP360 Phase 3 protocol (antidepressant taper and washout schedule), NCT05312151: https://cdn.clinicaltrials.gov/large-docs/51/NCT05312151/Prot_000.pdf
Antidepressant discontinuation prior to psilocybin, 233 TRD participants, Journal of Affective Disorders: https://www.sciencedirect.com/science/article/pii/S0022395624005855
EPIsoDE, psilocybin in treatment-resistant depression (washout design), JAMA Psychiatry: https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2846478
Cybin CYB003 Phase 3, adjunctive design, EU sites recruiting, NCT06793397: https://clinicaltrials.gov/study/NCT06793397
Cybin PARADIGM Phase 3 program initiation (adjunctive, no taper): https://www.businesswire.com/news/home/20241113365253/en/
AtaiBeckley BPL-003 Phase 2a in patients on SSRIs, CNS Drugs, 8 April 2026: https://ir.ataibeckley.com/news-releases/news-release-details/ataibeckleys-bpl-003-shows-rapid-durable-antidepressant-response
BPL-003 Phase 2a, four-part study, ClinicalTrials.gov, NCT05660642: https://clinicaltrials.gov/study/NCT05660642
LSD 5-HT2A receptor occupancy, Rigshospitalet, NCT05953038: https://clinicaltrials.gov/study/NCT05953038
Psilocybin Phase 3 in alcohol use disorder, CHU Nîmes, NCT07638553: https://clinicaltrials.gov/study/NCT07638553