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.
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.