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.
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.
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.
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 areto 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.
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.
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 preventativefor 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".
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.
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.
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.
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.
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.