How psilocybin, LSD, and 5-MeO-DALT work

This page explains what psilocybin, LSD, and 5-MeO-DALT actually are, why they seem to help with cluster headaches, and what a small preventive dose feels like. The goal is simply to demystify these compounds. None of this is required reading to follow the protocol, but many patients find it reassuring to know what they are taking and why it works.

What each substance is

Psilocybin

Psilocybin is a naturally occurring compound found in over 200 species of mushroom, most commonly Psilocybe cubensis (the species most patients grow at home). The mushrooms have been used by humans in religious and medicinal contexts for thousands of years. When you eat psilocybin mushrooms, your body quickly converts the psilocybin into a related compound called psilocin, which is what actually produces the effects. The mushrooms look like ordinary brown mushrooms with slender stems and small caps. They are usually eaten dried, brewed into a tea, or packed into capsules to mask the taste, which most people find unpleasant.

LSD

LSD (lysergic acid diethylamide) is a synthetic compound first made in 1938 by Albert Hofmann, a Swiss chemist. It is a lysergamide, derived from a fungus called ergot that grows on rye. It is not technically a tryptamine like psilocybin or 5-MeO-DALT, but it acts on the same brain receptors and produces broadly similar effects. LSD is one of the most potent psychoactive substances known. A single recreational dose is around 100 micrograms, an amount roughly the size of a grain of salt. Because the doses are so small, LSD is usually sold soaked into small squares of blotter paper or as a dilute liquid solution.

5-MeO-DALT

5-MeO-DALT (N,N-diallyl-5-methoxytryptamine) is a synthetic tryptamine first formulated by the chemist Alexander Shulgin and made widely available around 2004. It is closely related to psilocybin and to other tryptamines naturally found in plants and animals. Patients first started using it for cluster headache in 2014 after the work of Mitchell Post showed it could be effective. It is sold as a fine, off-white powder, which is weighed on a milligram scale and put into a small gelatin capsule.

How they help with cluster headaches

The honest answer is that no one fully knows yet. But several pieces of the puzzle have come into focus.

They act on the same brain receptors as standard cluster medications. All three substances activate a wide variety of serotonin receptors. So does sumatriptan, the most commonly prescribed cluster abortive, and so do the older ergot-based cluster drugs (like methysergide and dihydroergotamine). The shared serotonergic pharmacology is one reason researchers have long suspected that these compounds might be effective for cluster headache.

They seem to act on the hypothalamus. Cluster headaches are believed to originate in the hypothalamus, a small region deep in the brain that controls the body clock. In a 2024 Danish brain-imaging study, ten chronic patients given psilocybin showed measurable changes in hypothalamic activity, and the patients whose hypothalamic connectivity changed the most were also the ones whose attacks dropped the most.^[1] This is the first direct evidence linking the benefit to the part of the brain thought to drive cluster headaches.

The therapeutic effect seems separate from the "trip". In the Yale randomized trial, the size of the psychedelic experience did not correlate with the size of the headache benefit.^[2] Patients who reported barely feeling the dose still got better. This is one reason patients can use very small, sub-psychedelic doses and still see results, and it is also why a non-hallucinogenic version of LSD (called BOL-148, or 2-bromo-LSD) has shown promising effects in a small German case series in cluster headache patients.^[3]

The benefit lasts longer than the drug. All three substances clear the body within hours, but the effect on cluster cycles can last weeks or months from a single round of doses. This is unusual: most cluster medications need to be taken every day to work. Researchers think these compounds may produce a longer-term change in how the headache-generating brain circuits behave,^[4] but the exact mechanism is still being studied.

What a small dose feels like

The doses used for cluster headache prevention are smaller than recreational doses. The aim is to get the medical benefit while keeping the psychoactive effects mild and manageable. For most patients, a preventive dose feels somewhat like having a glass or two of wine, with a slightly different quality.

Each substance has its own character. The descriptions below are guiding but may vary from person to person.

Psilocybin (around 0.5 g of dried mushrooms)

• Onset: 20 to 60 minutes after eating.
• Duration: 4 to 6 hours.
• Common feelings: a soft warmth in the body, mild relaxation, mood lifted slightly, sometimes a touch of giggles. Colours might appear more vibrant, things might seem to breathe a little or take on patterned texture, and music can sound richer and induce stronger emotions. Light closed-eye visuals are possible if you are sensitive.
• Things to know: mild nausea is common in the first hour. Take on a near-empty stomach for cleaner absorption. The taste is unpleasant; tea or capsules help.

LSD (around 25 to 50 micrograms)

• Onset: 30 to 90 minutes.
• Duration: 4 to 8 hours, longer than psilocybin even at small doses.
• Common feelings: a soft warmth in the body, mild relaxation, mood lifted slightly, sometimes a touch of giggles. Colours might appear more vibrant, things might seem to breathe a little or take on patterned texture, and music can sound richer and induce stronger emotions. Light closed-eye visuals are possible if you are sensitive.
• Things to know: because LSD lasts longer, plan a half-day with no obligations. Effects can come on slowly.

5-MeO-DALT (around 15 mg)

• Onset: about 10 minutes.
• Duration: about 2 hours.
• Common feelings: marked drowsiness and intense relaxation. The most common reported side effect is a feeling of cold fingers and toes (in 41% of survey respondents), and 33% of patients in the survey reported no side effects at all.^[5]
• Things to know: this is the mildest of the three psychologically. Most patients describe it as barely noticeable. You usually return to normal functioning within 2 hours.

What "rebound" or "slap-back" attacks are

Some patients experience an unusual phenomenon in the days right after taking a preventive dose: instead of fewer attacks, they get worse attacks for a day or two. Patients call these "rebound" headaches. They can be distressing, but they are temporary, and many patients report them as a sign that the treatment is working. Better days usually follow within a few days.

If you experience a severe rebound or slapback, going back to triptans or other interfering medications can undo the treatment, so use oxygen or DMT for relief if you have access to those. Otherwise, check out these alternative methods.

References

1. ↩ Madsen MK, Petersen AS, Stenbæk DS, et al. (2024). CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity. Headache, 64(1), 55–67. doi:10.1111/head.14656
2. ↩ Schindler EAD, Sewell RA, Gottschalk CH, et al. (2022). Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: results from a randomized, double-blind, placebo-controlled trial. Headache, 62(10), 1383–1394. doi:10.1111/head.14420
3. ↩ Karst M, Halpern JH, Bernateck M, Passie T (2010). The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: An open, non-randomized case series. Cephalalgia, 30(9), 1140–1144. doi:10.1177/0333102410363490
4. ↩ Schindler EAD, Sewell RA, Gottschalk CH, Flynn LT, Zhu Y, Pittman BP, et al. (2024). Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial. Journal of the Neurological Sciences, 460, 122993. doi:10.1016/j.jns.2024.122993
5. ↩ Post M (2015). Cluster headache patient survey: 5-MeO-DALT. Self-published.