The Best Treatment for the Most Painful Medical Condition Is Illegal

By Alfredo Parra 🔸 @ 2025-12-17T11:13 (+58)

This is a linkpost to https://www.project-syndicate.org/commentary/psychedelic-drugs-should-be-legal-for-cluster-headache-by-peter-singer-2025-12

Peter Singer's latest column on Project Syndicate is about cluster headaches.

Sufferers of cluster headaches, also known as "suicide headaches," will do anything to stop what is possibly the most painful condition known to medicine, including using illegal drugs like psilocybin and LSD. Given strong evidence that psychedelics work, why aren't doctors allowed to prescribe them?

He also urges readers to sign our open letters on clusterfree.org. Please sign and ask others to sign.

Henry Howard🔸 @ 2025-12-18T12:30 (+9)

From a medical perspective this seems a bit daft

"Patients have reported anecdotally that vaporized DMT, another psychedelic drug, aborts attacks seconds after they begin (there are no published studies of this effect)".

In medicine you quickly learn that anectode is extremely unreliable and the average person is positively busting to attribute cause and effect to whatever they just experienced. Every homeopathic remedy/energy healer/prayer/crystal/snake oil has its die-hards who will give you convincing anectodes of immediate success, so doctors become rightly extremely skeptical about these stories.

The actual evidence he provides is this review of some case studies and surveys and 4 clinical trials but which have pretty low numbers. The review itself says:

"The small number of participants in each study limits reliability and generalizability of the findings. Even with ongoing work, differences in dosing regimens and outcomes among studies will limit the consolidation of findings"

Combined with the small risk of psychosis from psilocybin I understand why health systems wouldn't want to rush into mainstreaming them as treatment.

Alfredo Parra 🔸 @ 2025-12-18T14:27 (+10)

Thanks for your comment!

It is true that published studies on psychedelics are few and small. Hopefully that will change but, currently, investment into cluster headache is minute relative to its severity and prevalence. 

There are no studies on DMT in particular (though one survey is being carried out at Yale). However, we've argued that the little evidence we have on DMT specifically should be taken very seriously (which is what motivates the Yale group).

In medicine you quickly learn that anectode is extremely unreliable and the average person is positively busting to attribute cause and effect to whatever they just experienced. Every homeopathic remedy/energy healer/prayer/crystal/snake oil has its die-hards who will give you convincing anectodes of immediate success, so doctors become rightly extremely skeptical about these stories.

I think this definitely does not apply to DMT for CH. As mentioned in the post I linked above, patients can report going from experiencing the worst possible pain to being completely pain free within seconds of inhaling DMT. The cause and effect could not be any clearer. (There are also other statistical ways to quantify the reliability of anecdotes, see e.g. here.)

The actual evidence he provides is this review of some case studies and surveys and 4 clinical trials but which have pretty low numbers. The review itself says: "The small number of participants in each study limits reliability and generalizability of the findings. Even with ongoing work, differences in dosing regimens and outcomes among studies will limit the consolidation of findings"

(And yet it's worth pointing out that two of the three co-authors of that review, namely Christopher Gottschalk and Emmanuelle Schindler, are among the strongest supporters of psychedelic treatments for CH. Gottschalk is the Director of Headache Medicine at Yale and immediate past president at the Alliance for Headache Disorders Advocacy.)

Combined with the small risk of psychosis from psilocybin I understand why health systems wouldn't want to rush into mainstreaming them as treatment. 

How big is the risk of psychosis at low doses, and how does it compare to experiencing literally the worst possible pain, day in and day out?

I've been thinking about / working on cluster headaches since summer 2024, not just reading the academic literature but also following support groups online and talking to patients directly. There's no doubt in my mind that psychedelics help many patients enormously, and at low doses for most patients. I know some patients who decide not to take psychedelics, but we should give those who do want to use them the right to try them without any legal repercussions.

Henry Howard🔸 @ 2025-12-19T00:34 (+9)

patients can report going from experiencing the worst possible pain to being completely pain free within seconds of inhaling DMT

If that were reliably true then it wouldn't be hard to show it in a clinical trial. Instead the results seemed to show a little reduction in attack frequency, rather than episode cessation.
 

Other factors that skew anectodes to be unreliable:

  • The placebo effect is powerful and everyone underestimates it
  • People tend to exaggerate for effect (even when not intending to deceive). Someone saying "it got better in seconds" they might mean they started to feel it getting better within seconds but it didn't totally resolve for minutes or hours.
  • people tend to take things when symptoms are especially bad, which means whatever they do, things are likely to get better afterwards (regression to the mean, peaks and troughs)
Curran Janssens @ 2025-12-27T02:51 (+7)

The effect size is incredible and the percentage of people for whom it's effective for is very large. 

Yes, we agree that it wouldn't be hard to show in a clinical trial. The reasons why it hasn't been taken through trials are a massive failure of incentives - how many millions would be expected to take a (Schedule I) substance through clinical trials, all for a drug that can't be patented? (Though I do believe a solid return on investment is possible, especially with orphan drug designation and the uniquely high safety and efficacy profile that low dose DMT has for cluster headaches)

For the first time this year, a company will conduct clinical trials on a psychedelic preventative for cluster headaches, for which they've raised 6 million. I expect it to be very effective. Sadly, the uptake time makes it not possible to hit generally accepted headache abortive endpoints. A significant reason for them being able to raise this money is their already developed unique analogue, allowing them to have a composition of matter patent - something not possible for plain DMT. 

To go from Hell, back to baseline in a few moments would be an incredible placebo. And for people who have tried hundreds of treatments with no such placebo, it becomes apparent how real such an effect is.

I have seen a friend in the middle of a cluster headache try DMT for the first time and go from 7/10 pain (on an exponential scale - curled up in a ball in pain) to a 2/10 pain and back to talking normally in just a few seconds. They had never experienced such a quick resolution of pain in any of their ~100 headaches, which normally drag on at some level for hours. They now keep this DMT pen on them at all times, calling it their headache "epi-pen".

This is not a placebo effect.  

Henry Howard🔸 @ 2025-12-27T10:02 (+8)

“The effect size is incredible and the percentage of people for whom it's effective for is very large” - What’s the source for this?

Impressive anectodes, but we see a lot of those in medicine. Trial or it didn’t happen.

NickLaing @ 2025-12-27T10:10 (+27)

Comments like this @Alfredo Parra 🔸  "There's no doubt in my mind that psychedelics help many patients enormously, and at low doses for most patients. " and this @Curran Janssens "This is not a placebo effect." have updated me a little against the clusterfree initiative and this treatment specifically. This is not a good scientific approach, and mirrors language from patient lobby groups I've seen that often turns out to be incorrect or at least grossly overstated

This could still be placebo effect. After being a practising doctor for many years, I've experienced the power of the brain so many times. I've seen conversion disorder here in Uganda multiple times that's so extreme that when someone is poked with a sharp needle (and bleed) in multiple places there is zero pain reaction. Obviously we thought there was something serious going on in these cases but every time it turned out to be a strong psychological effect.

I agree with @Henry Howard🔸 , this probably shouldn't be legal yet. I wouldn't call the evidence "strong" yet until we get a well powered RCT vs. the best pain relief options currently available. "Trial or it didn't happen" as henry says is super important here, and this needs happen before any treatment becomes an encouraged, widespread norm.

If the effect is really as strong as claimed, you wouldn't even need 100 patients for an RCT. Perhaps clusterfree could even make this happen faster

Curran Janssens @ 2025-12-27T19:35 (+12)

Thank you both for the care to offer your time and responses on this matter. You're right that anecdotes are often unreliable and that rigor matters, but when someone mid-attack goes from fetal position to conversational in 30 seconds—and this happens repeatedly across independent patients who've tried dozens of ineffective treatments—the usual confounds don't apply.

To go from a feeling worse than torture, to totally okay in a few moments is not any standard placebo effect. Such immediate effect sizes of this magnitude are not something that placebos do. What do placebo responses actually look like for cluster headaches? From the sumatriptan RCT: 3% were pain-free at 10 minutes after placebo. The reported DMT effect (complete resolution in seconds, repeatedly, across independent patients) is orders of magnitude outside that envelope. Cluster attacks last 15–180 minutes. When someone experiences complete resolution in seconds neither placebo nor regression to the mean explains it.

The only FDA-approved acute treatment for cluster headache (subcutaneous sumatriptan) is a sulfonated DMT derivative that works via serotonin receptor agonism. DMT's efficacy is not a speculative hypothesis but a pharmacological expectation.

The evidence is clear that serotonergic psychedelics are extremely effective at the prevention and abortion of cluster headaches. We see this in Psilocybin (an RCT), in LSD, in BOL-148, and in 5-MEO-DALT. Even with zero specific evidence of anyone trying DMT, the prior should actually be quite high that DMT would have an effect for cluster headaches. But we do have evidence. 30 years of people ending their torture with a fast and reliable treatment. We have spent many hours asking about many kinds of treatments with many patients. No class of treatment compares to serotonergic psychedelics. 

As Bob Wold, who founded ClusterBusters in 2002 says:

"One inhalation [of DMT] will end the attack for most people. Everybody is reporting the exact same thing. […] It could end that attack in less than a minute. […] You can take one inhalation, you can wait 30 seconds, and if that cluster is not gone completely, then you know it's time to take another inhalation. You don't have to wait 2h into a psilocybin trip."

I want to mention again that DMT is a Schedule I substance. Schedule I classification requires difficult regulatory approval and specialized DEA licenses, and DMT's unpatentable status means no company has financial incentive to fund trials. This is why we see investment only when the patent barrier is solved—investors committed $26 million this year to develop a psilocin analog (Conjugated Psilocin) specifically for chronic cluster headache, betting on the same serotonergic tryptamine mechanism.

Regarding psychosis risk: DMT has already been administered to 100+ participants across multiple Phase I/II depression trials, with systematic reviews finding no serious adverse events and no prolonged psychotic reactions in controlled settings—the risk at therapeutic doses with psychiatric screening appears very low, not speculative.

Solutions of this magnitude deserve to be legal for compassionate use. The worst case of permission to try is a 15-minute experience they chose to risk. The worst case of prohibition is years of agony they had no choice in. For this body of evidence, I am a staunch supporter of letting people try what has become known in the cluster headache community as a miracle treatment.

Henry Howard🔸 @ 2025-12-27T23:15 (+8)

“From the sumatriptan RCT: 3% were pain-free at 10 minutes after placebo.”

This is an irrational comparison. You’re comparing your best case scenario anecdote to the results of an RCT.

It’s possible that one of those 3% of people would have an anecdote for sumatriptan as convincing as yours: causing rapid resolution of their headache. That anecdote would not be representative.

I’m not saying you’re wrong about psychedelics and cluster headache. I desperately hope you’re right and there is an easy fix. Anecdote leads people astray constantly and we have to have a high suspicion of it.

Curran Janssens @ 2025-12-28T01:23 (+10)

This is not based on an anecdote. I've been researching cluster headaches for a year+ before this independent anecdote occured. I would have said the same thing before I saw it work first hand. An anecdote should not be evidence by itself, but I hope we can be charitable and recognize that when offered in additon to many other forms of evidence that it is not reason to disagree by itself.

If I can sum up the evidence:

1. The only FDA approved acute cluster headache treatment is an analogue (!) of DMT, with the same underlying mechanism  of 5-HT1B/1D agonism

2. Many published studies point towards multiple classes of serontonergic psychedelics being very effective for preventing and aborting cluster headaches

3. The leading advocacy org ClusterBusters has been advocating for the use of DMT for several years

4. The effect is immediate and massive to a scale not seen in any studied placebo effect and widely recognized among people who try it

 

May we examine the whole body of research at once and recognize that yes, any lone anecdote or piece of the puzzle would not be sufficient to have this level of confidence. And how blessed we are to find ourselves with many independent sources of confidence (mechanistic rationale, drug class success, broad advocacy agreement) that we may rely on rather than a lone anecdote.

It's also quite unlikely that the 3% placebo figure was complete pain abortion in seconds - as it states this is after 10 minutes and cluster headaches are not known to suddenly end on their own as we see with DMT. Within 10 minutes I'd actually expect 3%+ to naturally come to an end.

I'd love to see evidence like this for similarily terrible diseases. Placebo effects are much more common for lower intensities of pain than shockingly painful ailments like Trigeminal Neuralgia, Kidney Stones and Appendicitis.

I am happy to say that an RCT would provide a standard of evidence not currently available - but to think that we should not offer this as an option to any cluster headache patient who wants to try would be quite a tragedy. 


 

NickLaing @ 2025-12-28T06:41 (+6)

I do see that as a string argument, but i still think drugs should only go to market legally when both safety and efficacy has been proven in well enough powered RCTs. The risk to the medical profession and the reputation of the drug production industry is just too high to allow any less i think. There's no reason a fast tracked RCT couldn't get this sorted in a year and that seems like a reasonable way forward.

The RCT should also be vs. tryptans and not vs. placebo. I'm not sure why the previous small trials were not done vs. standard best practice, that seems odd to me?

 If I was sitting in the FDA reviewing this i would still be pretty nervous about making an exception.

Curran Janssens @ 2025-12-28T19:41 (+1)

It is wonderful to not know what a cluster headache feels like. For to feel a single attack is to know what is one of the greatest tragedies humanity has ever faced.

If these approached anything even 10x worse than the worst pain I’ve ever felt, I might agree with you. Sadly this is not our world. There is no way to understand what a cluster headache feels like without experiencing one.

Suffering exists on an exponential scale, and these truly represent the end of this spectrum. This is an affliction that can be understood as worse than torture — the only pain that routinely scores 10/10 in comparative studies.

If it took an FDA approved RCT to get a family member free from torture I would not wait. And if it was illegal or broke FDA norms that would not stop me.

A 'fast-tracked year' ignores the shockingly high regulatory burden. For DMT, a Schedule I substance, delivered via an unvalidated inhaler requiring parallel FDA device review, tested against an active comparator which demands larger sample sizes, in a rare disease where existing trials took years to recruit 10-16 patients: year one gets you DEA licensing, device validation, and perhaps your first enrollees. A fast tracked timeline to complete a well-powered RCT—just the trial, just the data— may be something like 3-5 years. And that's not approval. That's permission to begin the approval process, which multiplies the timeline again: Phase 3 confirmation, FDA review, DEA rescheduling, state-level legal changes. A record setting entire process might be 5-10 years at minimum before a prescription could be written. The MDMA program had Breakthrough designation, $130 million, two favorable Phase 3 trials, twenty years—and got rejected last August. This problem deserves a novel solution.

You are absolutely right that until an FDA approved product exists that can be recommended by doctors who also rely on RCTs, we cannot expect this problem to go away. May we work to help any RCT become possible. And until that happens, every intervention with evidence as promising as DMT deserves to be accessible, or at the very least not illegal.

NickLaing @ 2025-12-28T20:07 (+4)

why does it take years to recruit as small number of patients if sufferers are so enthusiastic about this as a potential treatment?

NickLaing @ 2025-12-28T20:04 (+2)

First.."If it took an FDA approved RCT to get a family member free from torture I would not wait. And if it was illegal or broke FDA norms that would not stop me."

 I agree with this. even if it might be placebo if a family member was this convinced of something working, I would probably get it for them illegally. This isn't related by my lights to the question of following proper process.

Second.. "suffering exists on an exponential scale, and these truly represent the end of this spectrum. This is an affliction worse than torture. Survivors of both have said cluster headaches were worse."

this is a tragedy for sure but I think we have to be careful not to make arguments like this is the only situation where delay causes lots of suffering.

recently a malaria vaccine rollout sat waiting a while for FDA approval. every day delay the might have cost tens of lives (just a guess). I'm not saying waiting for FDA approval is the best situation, but this is not a special case, tragic delays happen all the time.

Curran Janssens @ 2025-12-29T05:31 (+3)

Upon learning of a tragedy, one response is to note other similar tragedies, say it "happens all the time”, and accept it.

The world's most painful disease has what appears to be an effective treatment. It cannot be prescribed. It is illegal to try. I work backwards from the view that this is not acceptable.

The rules we create for our society are not set in stone. We can demand that our governments recognize the extremes of suffering.

Three societal frameworks fail to account for something so terrible as a cluster headache.

The first is our criminal legal system. DMT is a Schedule I substance, classified as having "no accepted medical use". This makes it illegal to possess or administer regardless of medical intent. We are asked to trust that DEA scheduling decisions correctly identify which substances should be categorically forbidden.

The second is our medical regulatory system. The FDA requires rigorous evidence of safety and efficacy before a treatment can enter medical practice. This system asks us to trust that these evidentiary barriers, however expensive and lengthy to clear, are necessary protections.

The third are the economic structures that determine which treatments get developed. Pharmaceutical companies invest in the multi-million dollar studies the FDA requires only when they can expect sufficient returns. Insurance will pay millions to save a life yet almost nothing to prevent extreme suffering. 

Where an effective treatment is illegal to obtain, impossible to prescribe, and not incentivized to develop, we find a massive failure. Insurers should pay for preventing extreme suffering the way they pay for extending life. The RCTs would pay for themselves.

And until then, patients should not be criminals for seeking relief from the most painful disease known to medicine.

Alfredo Parra 🔸 @ 2025-12-28T19:28 (+3)

Thanks for sharing your thoughts! While I'm obviously sad that you've updated negatively, this exchange has been very helpful for me to reflect on how to communicate my level of confidence in these treatments, especially given the little data we have from RCTs specifically. The total evidence still looks overall highly compelling to me (I wouldn't be working on this ~full time otherwise), but I'll work on improving my communication (and generating more scientific evidence).

The main thing I'd like to say is that I'm really not committed to psychedelics as an intervention (since you brought up the lobbyist language), and I'm particularly excited and hopeful about non-hallucinogenic analogues (such as BOL-148 and Conjugated Psilocin), as well as about non-pharmaceutical interventions, which we're also exploring. Ultimately, I just want patients to have universal access to treatments that safely and effectively prevent or abort their attacks. Currently, I sincerely believe those happen to be indoleamines.

If the effect is really as strong as claimed, you wouldn't even need 100 patients for an RCT. Perhaps clusterfree could even make this happen faster

Absolutely agree, and we're actively thinking about how to do this!

cube_flipper @ 2025-12-19T16:09 (+5)

For what it is worth (anecdotal, I know) I have personally (face to face) spoken to no less than three people who have used DMT to knock out a cluster headache and could describe the process in great detail. The causality is pretty noticeable and clear.

Henry Howard🔸 @ 2025-12-19T21:35 (+11)

Then it should be quite easy to show this benefit in clinical trials and it's suspicious that it hasn't happened

Alfredo Parra 🔸 @ 2025-12-20T08:02 (+3)

Why suspicious? The fact that DMT aborts cluster headaches is a pretty recent discovery. The word is just beginning to spread among sufferers. And there are very few researchers working on this topic, and very little funding generally, and it can be pretty difficult to get all the permissions needed to run trials using psychedelics. (I wouldn't be surprised if Schindler's group at Yale was running the DMT survey as a preliminary step to justify running a proper trial. Note that Schindler "is believed to be the only researcher in the United States studying psychedelics in headache disorders.")

Henry Howard🔸 @ 2025-12-20T10:00 (+6)

This report from 2006 has similarly high numbers of surveyed people saying that psilocybin or LSD aborted their headaches https://pubmed.ncbi.nlm.nih.gov/16801660/
That's 19 years for someone to do a controlled trial of cessation of cluster headaches using psilocybin or LSD vs placebo or triptan control. Wouldn't have to very big numbers either if the anecdotes are to be believed.

I guess your theory is that there have been too many funding and legal blocks to get this done in that 19 years. Seems hard to believe. Terrible if true.

If it is true, would recommend you focus on this as your core advocacy point: we need a placebo-controlled cluster cessation trial of psychedelics (rather than just prophylaxis). Saying "The Best Treatment for the Most Painful Medical Condition Is Illegal" is an unproven statement and makes you seem unserious

Alfredo Parra 🔸 @ 2025-12-20T12:49 (+8)

I understand it seems hard to believe! And yes, I'm motivated to support / advocate for RCTs and I'm developing various ideas with some collaborators (not just involving psychedelics). I agree that more data published in peer-reviewed journals is very much needed.

I still genuinely believe that the funding and legal barriers are very difficult to overcome (plus other barriers). A good resource on this topic is the book Psychedelic Outlaws (describing the history of psychedelic use and research for CH). This deep research by Claude may also provide useful context: Why psychedelic research for cluster headaches has stalled despite decades of patient evidence. It concludes:

The documented barriers to psychedelic cluster headache research reveal systemic failures across every institution that might otherwise advance treatment. Schedule I classification adds years to research timelines. NIH has invested almost nothing in cluster headache specifically. Pharmaceutical companies see no return in treatments requiring only three doses annually. Academic institutions impose unique scrutiny on psychedelic protocols. Patient recruitment struggles with rarity, episodic presentation, and placebo reluctance.

The BOL-148 story crystallizes the tragedy: a non-hallucinogenic compound showed unprecedented efficacy in 2010, yet required 13 years to enter Phase 1 trials because it fell between orphan drug and commercial viability. As Bob Wold observed: "You can't introduce transformative medicine into a broken healthcare system." The gap between patient discovery in 1998 and the current state of research—with perhaps one dedicated US researcher and trials measured in dozens of participants—represents what Halpern called "a process that has begun 40 years too late."