Comments like this @Alfredo Parra šøāThereās no doubt in my mind that psychedelics help many patients enormously, and at low doses for most patients. ā and this @Curran JanssensāThis is not a placebo effect.ā 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 Iāve 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, Iāve experienced the power of the brain so many times. Iāve seen conversion disorder here in Uganda multiple times thatās 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 Howardšø , this probably shouldnāt be legal yet. I wouldnāt call the evidence āstrongā yet until we get a well powered RCT vs. the best pain relief options currently available. āTrial or it didnāt happenā 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 wouldnāt 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. Youāre right that anecdotes are often unreliable and that rigor matters, but when someone mid-attack goes from fetal position to conversational in 30 secondsāand this happens repeatedly across independent patients whoāve tried dozens of ineffective treatmentsāthe usual confounds donāt 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 15ā180 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. DMTās 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:
āOne inhalation [of DMT] will end the attack for most people. Everybody is reporting the exact same thing. [ā¦] It could end that attack in less than a minute. [ā¦] You can take one inhalation, you can wait 30 seconds, and if that cluster is not gone completely, then you know itās time to take another inhalation. You donāt have to wait 2h into a psilocybin trip.ā
I want to mention again that DMT is a Schedule I substance. Schedule I classification requires difficult regulatory approval and specialized DEA licenses, and DMTās unpatentable status means no company has financial incentive to fund trials. This is why we see investment only when the patent barrier is solvedāinvestors 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/āII depression trials, with systematic reviews finding no serious adverse events and no prolonged psychotic reactions in controlled settingsāthe 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.
āFrom the sumatriptan RCT: 3% were pain-free at 10 minutes after placebo.ā
This is an irrational comparison. Youāre comparing your best case scenario anecdote to the results of an RCT.
Itās 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.
Iām not saying youāre wrong about psychedelics and cluster headache. I desperately hope youāre 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. Iāve 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/ā1D 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.
Itās also quite unlikely that the 3% placebo figure was complete pain abortion in secondsāas 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 Iād actually expect 3%+ to naturally come to an end.
Iād 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 availableābut 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. Thereās no reason a fast tracked RCT couldnāt 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. Iām 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 Iāve 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 āfast-tracked yearā 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 RCTājust the trial, just the dataā may be something like 3-5 years. And thatās not approval. Thatās 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 yearsāand 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..āIf 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.ā
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 isnāt related by my lights to the question of following proper process.
Second.. āsuffering 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.ā
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). Iām 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 āhappens all the timeā, and accept it.
The worldās 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 āno accepted medical useā. 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 Iām obviously sad that youāve 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 wouldnāt be working on this ~full time otherwise), but Iāll work on improving my communication (and generating more scientific evidence).
The main thing Iād like to say is that Iām really not committed to psychedelics as an intervention (since you brought up the lobbyist language), and Iām particularly excited and hopeful about non-hallucinogenic analogues (such as BOL-148 and Conjugated Psilocin), as well as about non-pharmaceutical interventions, which weāre 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 wouldnāt even need 100 patients for an RCT. Perhaps clusterfree could even make this happen faster
Absolutely agree, and weāre actively thinking about how to do this!
Comments like this @Alfredo Parra šø āThereās no doubt in my mind that psychedelics help many patients enormously, and at low doses for most patients. ā and this @Curran Janssens āThis is not a placebo effect.ā 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 Iāve 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, Iāve experienced the power of the brain so many times. Iāve seen conversion disorder here in Uganda multiple times thatās 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 Howardšø , this probably shouldnāt be legal yet. I wouldnāt call the evidence āstrongā yet until we get a well powered RCT vs. the best pain relief options currently available. āTrial or it didnāt happenā 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 wouldnāt 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. Youāre right that anecdotes are often unreliable and that rigor matters, but when someone mid-attack goes from fetal position to conversational in 30 secondsāand this happens repeatedly across independent patients whoāve tried dozens of ineffective treatmentsāthe usual confounds donāt 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 15ā180 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. DMTās 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:
āOne inhalation [of DMT] will end the attack for most people. Everybody is reporting the exact same thing. [ā¦] It could end that attack in less than a minute. [ā¦] You can take one inhalation, you can wait 30 seconds, and if that cluster is not gone completely, then you know itās time to take another inhalation. You donāt have to wait 2h into a psilocybin trip.ā
I want to mention again that DMT is a Schedule I substance. Schedule I classification requires difficult regulatory approval and specialized DEA licenses, and DMTās unpatentable status means no company has financial incentive to fund trials. This is why we see investment only when the patent barrier is solvedāinvestors 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/āII depression trials, with systematic reviews finding no serious adverse events and no prolonged psychotic reactions in controlled settingsāthe 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.
āFrom the sumatriptan RCT: 3% were pain-free at 10 minutes after placebo.ā
This is an irrational comparison. Youāre comparing your best case scenario anecdote to the results of an RCT.
Itās 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.
Iām not saying youāre wrong about psychedelics and cluster headache. I desperately hope youāre 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. Iāve 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/ā1D 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.
Itās also quite unlikely that the 3% placebo figure was complete pain abortion in secondsāas 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 Iād actually expect 3%+ to naturally come to an end.
Iād 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 availableābut 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. Thereās no reason a fast tracked RCT couldnāt 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. Iām 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 Iāve 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 ā the only pain that routinely scores 10ā10 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 āfast-tracked yearā 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 RCTājust the trial, just the dataā may be something like 3-5 years. And thatās not approval. Thatās 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 yearsāand 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..āIf 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.ā
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 isnāt related by my lights to the question of following proper process.
Second.. āsuffering 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.ā
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). Iām 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 āhappens all the timeā, and accept it.
The worldās 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 āno accepted medical useā. 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 Iām obviously sad that youāve 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 wouldnāt be working on this ~full time otherwise), but Iāll work on improving my communication (and generating more scientific evidence).
The main thing Iād like to say is that Iām really not committed to psychedelics as an intervention (since you brought up the lobbyist language), and Iām particularly excited and hopeful about non-hallucinogenic analogues (such as BOL-148 and Conjugated Psilocin), as well as about non-pharmaceutical interventions, which weāre 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 weāre actively thinking about how to do this!