There are no studies on DMT in particular (though one survey is being carried out at Yale). However, weâve 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/âenergy healer/âprayer/âcrystal/âsnake 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: âThe 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 findingsâ
(And yet itâs 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 wouldnât 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?
Iâve been thinking about /â working on cluster headaches since summer 2024, not just reading the academic literature but also following support groups online and talking to patients directly. Thereâs 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.
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 wouldnât 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:
People tend to exaggerate for effect (even when not intending to deceive). Someone saying âit got better in secondsâ they might mean they started to feel it getting better within seconds but it didnât 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)
The effect size is incredible and the percentage of people for whom itâs effective for is very large.
Yes, we agree that it wouldnât be hard to show in a clinical trial. The reasons why it hasnât been taken through trials are a massive failure of incentivesâhow many millions would be expected to take a (Schedule I) substance through clinical trials, all for a drug that canât 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 theyâve 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 patentâsomething 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 7â10 pain (on an exponential scaleâcurled up in a ball in pain) to a 2â10 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 âepi-penâ.
Comments like this @Alfredo Parra đžâThereâs no doubt in my mind that psychedelics help many patients enormously, and at low doses for most patients. â and this @Curran JanssensâThis is not a placebo effect.â 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 Iâve 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, Iâve experienced the power of the brain so many times. Iâve seen conversion disorder here in Uganda multiple times thatâs 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 Howardđž , this probably shouldnât be legal yet. I wouldnât call the evidence âstrongâ yet until we get a well powered RCT vs. the best pain relief options currently available. âTrial or it didnât happenâ as henry saysis 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 wouldnât even need 100 patients for an RCT. Perhaps clusterfree could even make this happen faster
Thank you both for the care to offer your time and responses on this matter. Youâre right that anecdotes are often unreliable and that rigor matters, but when someone mid-attack goes from fetal position to conversational in 30 secondsâand this happens repeatedly across independent patients whoâve tried dozens of ineffective treatmentsâthe usual confounds donât 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 15â180 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. DMTâs 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:
âOne inhalation [of DMT] will end the attack for most people. Everybody is reporting the exact same thing. [âŠ] It could end that attack in less than a minute. [âŠ] You can take one inhalation, you can wait 30 seconds, and if that cluster is not gone completely, then you know itâs time to take another inhalation. You donât have to wait 2h into a psilocybin trip.â
I want to mention again that DMT is a Schedule I substance. Schedule I classification requires difficult regulatory approval and specialized DEA licenses, and DMTâs unpatentable status means no company has financial incentive to fund trials. This is why we see investment only when the patent barrier is solvedâinvestors 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/âII depression trials, with systematic reviews finding no serious adverse events and no prolonged psychotic reactions in controlled settingsâthe 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.
âFrom the sumatriptan RCT: 3% were pain-free at 10 minutes after placebo.â
This is an irrational comparison. Youâre comparing your best case scenario anecdote to the results of an RCT.
Itâs 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.
Iâm not saying youâre wrong about psychedelics and cluster headache. I desperately hope youâre right and there is an easy fix. Anecdote leads people astray constantly and we have to have a high suspicion of it.
This is not based on an anecdote. Iâve 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/â1D 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.
Itâs also quite unlikely that the 3% placebo figure was complete pain abortion in secondsâas 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 Iâd actually expect 3%+ to naturally come to an end.
Iâd 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 availableâbut 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.
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. Thereâs no reason a fast tracked RCT couldnât 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. Iâm 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.
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 Iâve 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 âfast-tracked yearâ 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 RCTâjust the trial, just the dataâ may be something like 3-5 years. And thatâs not approval. Thatâs 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 yearsâand 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.
First..âIf 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.â
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 isnât related by my lights to the question of following proper process.
Second.. âsuffering 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.â
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). Iâm not saying waiting for FDA approval is the best situation, but this is not a special case, tragic delays happen all the time.
Upon learning of a tragedy, one response is to note other similar tragedies, say it âhappens all the timeâ, and accept it.
The worldâs 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 âno accepted medical useâ. 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.
Thanks for sharing your thoughts! While Iâm obviously sad that youâve 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 wouldnât be working on this ~full time otherwise), but Iâll work on improving my communication (and generating more scientific evidence).
The main thing Iâd like to say is that Iâm really not committed to psychedelics as an intervention (since you brought up the lobbyist language), and Iâm particularly excited and hopeful about non-hallucinogenic analogues (such as BOL-148 and Conjugated Psilocin), as well as about non-pharmaceutical interventions, which weâre 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 wouldnât even need 100 patients for an RCT. Perhaps clusterfree could even make this happen faster
Absolutely agree, and weâre actively thinking about how to do this!
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, weâve argued that the little evidence we have on DMT specifically should be taken very seriously (which is what motivates the Yale group).
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.)
(And yet itâs 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.)
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?
Iâve been thinking about /â working on cluster headaches since summer 2024, not just reading the academic literature but also following support groups online and talking to patients directly. Thereâs 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.
If that were reliably true then it wouldnât 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 âit got better in secondsâ they might mean they started to feel it getting better within seconds but it didnât 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)
The effect size is incredible and the percentage of people for whom itâs effective for is very large.
Yes, we agree that it wouldnât be hard to show in a clinical trial. The reasons why it hasnât been taken through trials are a massive failure of incentivesâhow many millions would be expected to take a (Schedule I) substance through clinical trials, all for a drug that canât 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 theyâve 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 patentâsomething 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 7â10 pain (on an exponential scaleâcurled up in a ball in pain) to a 2â10 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 âepi-penâ.
This is not a placebo effect.
âThe effect size is incredible and the percentage of people for whom itâs effective for is very largeââWhatâs the source for this?
Impressive anectodes, but we see a lot of those in medicine. Trial or it didnât happen.
Comments like this @Alfredo Parra đž âThereâs no doubt in my mind that psychedelics help many patients enormously, and at low doses for most patients. â and this @Curran Janssens âThis is not a placebo effect.â 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 Iâve 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, Iâve experienced the power of the brain so many times. Iâve seen conversion disorder here in Uganda multiple times thatâs 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 Howardđž , this probably shouldnât be legal yet. I wouldnât call the evidence âstrongâ yet until we get a well powered RCT vs. the best pain relief options currently available. âTrial or it didnât happenâ 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 wouldnât even need 100 patients for an RCT. Perhaps clusterfree could even make this happen faster
Thank you both for the care to offer your time and responses on this matter. Youâre right that anecdotes are often unreliable and that rigor matters, but when someone mid-attack goes from fetal position to conversational in 30 secondsâand this happens repeatedly across independent patients whoâve tried dozens of ineffective treatmentsâthe usual confounds donât 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 15â180 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. DMTâs 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:
âOne inhalation [of DMT] will end the attack for most people. Everybody is reporting the exact same thing. [âŠ] It could end that attack in less than a minute. [âŠ] You can take one inhalation, you can wait 30 seconds, and if that cluster is not gone completely, then you know itâs time to take another inhalation. You donât have to wait 2h into a psilocybin trip.â
I want to mention again that DMT is a Schedule I substance. Schedule I classification requires difficult regulatory approval and specialized DEA licenses, and DMTâs unpatentable status means no company has financial incentive to fund trials. This is why we see investment only when the patent barrier is solvedâinvestors 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/âII depression trials, with systematic reviews finding no serious adverse events and no prolonged psychotic reactions in controlled settingsâthe 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.
âFrom the sumatriptan RCT: 3% were pain-free at 10 minutes after placebo.â
This is an irrational comparison. Youâre comparing your best case scenario anecdote to the results of an RCT.
Itâs 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.
Iâm not saying youâre wrong about psychedelics and cluster headache. I desperately hope youâre right and there is an easy fix. Anecdote leads people astray constantly and we have to have a high suspicion of it.
This is not based on an anecdote. Iâve 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/â1D 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.
Itâs also quite unlikely that the 3% placebo figure was complete pain abortion in secondsâas 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 Iâd actually expect 3%+ to naturally come to an end.
Iâd 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 availableâbut 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.
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. Thereâs no reason a fast tracked RCT couldnât 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. Iâm 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.
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 Iâve 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 â the only pain that routinely scores 10â10 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 âfast-tracked yearâ 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 RCTâjust the trial, just the dataâ may be something like 3-5 years. And thatâs not approval. Thatâs 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 yearsâand 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.
why does it take years to recruit as small number of patients if sufferers are so enthusiastic about this as a potential treatment?
First..âIf 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.â
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 isnât related by my lights to the question of following proper process.
Second.. âsuffering 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.â
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). Iâm not saying waiting for FDA approval is the best situation, but this is not a special case, tragic delays happen all the time.
Upon learning of a tragedy, one response is to note other similar tragedies, say it âhappens all the timeâ, and accept it.
The worldâs 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 âno accepted medical useâ. 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.
Thanks for sharing your thoughts! While Iâm obviously sad that youâve 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 wouldnât be working on this ~full time otherwise), but Iâll work on improving my communication (and generating more scientific evidence).
The main thing Iâd like to say is that Iâm really not committed to psychedelics as an intervention (since you brought up the lobbyist language), and Iâm particularly excited and hopeful about non-hallucinogenic analogues (such as BOL-148 and Conjugated Psilocin), as well as about non-pharmaceutical interventions, which weâre 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.
Absolutely agree, and weâre actively thinking about how to do this!