TL;DR
- Microdose = sub-perceptual, taken on a schedule (typically every 3 days for 4-8 weeks). Logic: gradual mood and cognition shift over time.
- Macrodose = full psychedelic experience (~2-5 g dried mushrooms or 25 mg synthetic), typically 1-2 sessions with therapy. Logic: a single rewiring window plus integration.
- For diagnosed depression, macrodose has the strong evidence (Phase 2/3 trials). Microdose evidence is mixed: surveys positive, placebo-controlled trials mostly null.
- For mild mood, lifestyle support, comorbid anxiety: microdose is reasonable, lower-risk, easier to sustain.
- Macrodose requires preparation, sitter, integration. Microdose can be solo with a tracking practice. Both require sourcing and harm-reduction baseline.
Side-by-side comparison
| Dimension | Microdose | Macrodose |
|---|---|---|
| Typical dose (psilocybin) | 0.1-0.3 g dried (~1-3 mg synthetic) | 2-5 g dried (~10-30 mg synthetic) |
| Subjective experience | Sub-perceptual; subtle mood/focus shift | Full psychedelic experience, 4-6 hours |
| Schedule | Every 3 days, 4-8 weeks, then pause | 1-2 sessions per protocol; pause between |
| Setting required | Normal day (work, social) | Quiet room, sitter, prep, integration |
| Time commitment per dose | Minimal | ~8 hours session + 6+ hours therapy |
| Evidence base for depression | Surveys positive, placebo-controlled trials largely null | Phase 2/3 RCTs show significant antidepressant effect |
| Best fit conditions | Mild mood, focus, comorbid anxiety, ADHD adjunct | Treatment-resistant depression, end-of-life anxiety, addiction |
| SSRI compatibility | Blunted but functionally compatible | Requires tapering for therapeutic effect |
| Risk per dose | Low; mostly subjective | Higher; cardiovascular load, anxiety, dose error |
| Cost | Sourcing only | $1500-3000+ per regulated session (OR/CO) |
| Durability | Effects fade days after stopping | 3-6 months per session in responders |
Mechanism difference
Same receptor (5-HT2A), different scales:
- Microdose: partial 5-HT2A activation, sub-behavioral. Theoretical mechanisms include subtle mood lift via 5-HT2A tone, possible BDNF effect (not yet shown in vivo at microdose), and expectancy. The Szigeti 2021 self-blinded RCT (n=191) found microdose benefits matched placebo response, suggesting expectancy is a major driver.
- Macrodose: full 5-HT2A activation drives the experience. Default-mode network desynchronizes acutely. Post-session 30-day window of elevated BDNF and dendritic spine density supports therapy-driven re-encoding. Mystical-type experience scores correlate with outcome.
The two are not just “more or less of the same thing.” The mechanism logic is genuinely different. Macrodose creates a discrete event with a recovery window. Microdose creates a sustained low-level modulation.
Evidence base, head to head
| Study | Year | Type | Finding |
|---|---|---|---|
| Goodwin et al., COMPASS Phase 2b (macro) | 2022 | RCT n=233 TRD, 1× 25 mg | Significant MADRS reduction at week 3, sustained week 12 |
| Davis et al., JHU MDD (macro) | 2020 | RCT n=27, 2× 20-30 mg | 71% response, 54% remission at 4 weeks |
| Szigeti et al. (microdose) | 2021 | Self-blinded RCT n=191 | Microdose benefits matched placebo response |
| Hutten et al. Maastricht (microdose) | 2024 | Placebo-controlled LSD microdose | No significant mood effect vs placebo in healthy adults |
| Microdose for diagnosed depression placebo-controlled RCT | — | — | None published to date |
Read this honestly: macrodose has the evidence for depression. Microdose has surveys plus null placebo-controlled trials in healthy adults. The microdose-for-diagnosed-depression placebo-controlled trial is missing.
When each fits
Microdose fits when
- Your depression is mild to moderate, not treatment-resistant.
- You have comorbid anxiety, ADHD-spectrum, or focus issues.
- You cannot or will not commit to a full-dose session structure.
- You want to test whether the substance helps you at all before considering macrodose.
- You can run a 4-8 week protocol with objective tracking (PHQ-9, partner check-in, behavioral data).
Macrodose fits when
- You meet criteria for treatment-resistant depression.
- You have access (Oregon, Colorado, clinical trial, FDA expanded access).
- You can taper SSRI safely with prescriber.
- You can commit to preparation and integration sessions.
- You are not on lithium, MAOI, or have other hard contraindications.
Risk profile, side by side
| Risk | Microdose | Macrodose |
|---|---|---|
| Acute cardiovascular load | Minimal | Significant during dose |
| Bad-trip risk | Near zero (sub-perceptual) | Real; setting and sitter mitigate |
| HPPD (perception persistence) | Very low | Rare but documented |
| Mania risk in undiagnosed bipolar | Lower | Higher; screen carefully |
| SSRI tapering harm | Not required | Required for therapeutic effect; rebound depression real |
| Sourcing-related contamination | Same baseline | Same baseline; higher dose means higher consequence |
| Time-off-work cost | None | 1-2 days per session |
Stacking microdose and macrodose
Some patients use both: microdose protocol for ongoing maintenance, occasional macrodose session for the deeper reset. No clinical trial of this stacked approach. Common practice in regulated programs (Oregon facilitators sometimes recommend microdose between full-dose sessions).
Spacing rules apply: do not microdose for ~7 days before a macrodose session (tolerance and signal interference). Resume microdosing 4+ weeks after, once integration window has closed.
FAQ
Which is better for depression?
For diagnosed depression, especially treatment-resistant, the evidence favors macrodose. For mild mood and lifestyle, microdose is reasonable but the controlled trials suggest most of the effect may be expectancy.
Can I just microdose forever?
Tolerance builds within days. The standard protocol pauses every 4-8 weeks. Indefinite daily microdosing both reduces effect and removes the safety of a re-evaluation window.
If microdose did not work, will macrodose work?
Possibly. Different mechanism scale. Many patients who got nothing from microdose responded to macrodose in the trial cohorts. The evidence supports trying macrodose if microdose was insufficient and you meet criteria.
Can I do macrodose without therapy?
You can dose, but you give up the part most predictive of outcome. The trials embed the dose in 2-3 prep sessions and 3-6 integration sessions. The integration is where the change consolidates.
What about LSD micro vs macro for depression?
LSD has less Phase 2/3 depression evidence than psilocybin. The microdose Maastricht trial used LSD and was null. For depression specifically, the evidence base points to psilocybin macrodose.
Where can I learn more about each?
For microdose protocols, see our how-to-microdose course. For macrodose, see treatment-resistant depression and microdosing for depression.
