Treating Cluster Headaches Using N,N-DMT and Other Tryptamines

To ex­tend this re­cent EA Fo­rum Post, I wanted to share the re­sults of Qualia Re­search In­sti­tute’s re­search into us­ing tryptamines to abort and pre­vent cluster headaches. While the quotes and statis­tics con­tained here can provide some no­tion of the pain ex­pe­rienced by cluster headache suffer­ers, I think it is truly uni­mag­in­able. This re­port con­tains spe­cific in­ter­ven­tions to be pur­sued in both a philan­thropic and for-profit busi­ness ca­pac­ity. While for-profit op­tions are be­yond our scope, those in­ter­ested in sup­port­ing philan­thropic in­ter­ven­tions should con­sider donat­ing to ClusterBusters (the most im­por­tant non­profit ded­i­cated to re­search­ing treat­ments for cluster headaches), or QRI (which does foun­da­tional re­search on ways to re­duce in­tense suffer­ing).

Mis­sion: In­stantly and safely abort cluster headaches and treat mi­graines, the #2 and #10 (re­spec­tively) most painful med­i­cal con­di­tions ac­cord­ing to NHS. Em­pha­sis is placed on chronic cluster headaches, which ac­count for as much as 80% of all clusters and cur­rently lack an effec­tive treat­ment op­tion.


I. Prob­lem:

“Even child birth is 1/​10th the pain of a cluster headache, se­ri­ously this name needs to change… call it ul­tra su­per mi­graine.” (source)
  • A back of the en­velope calcu­la­tion in­di­cates there are roughly 14 thou­sand peo­ple en­dur­ing a cluster headache right now.[1]

  • 14.2% of US adults 18 or older re­ported hav­ing mi­graine or se­vere headache in the pre­vi­ous 3 months in the 2012 NHIS. The over­all age-ad­justed 3-month prevalence of mi­graine in fe­males was 19.1% and in males 9.0%, but varied sub­stan­tially de­pend­ing on age. (source)

  • Cur­rent treat­ments are ei­ther in­effec­tive, costly, un­safe, or some com­bi­na­tion of the three. The most effec­tive treat­ments available for cluster headaches in­clude oxy­gen, which re­quires the pa­tient to carry an oxy­gen tank with them at all times, and trip­tans, which can be used a max­i­mum of three times daily (an is­sue for chronic suffer­ers es­pe­cially) and have side effects from pain to heart at­tack and stroke. The most effec­tive treat­ments for mi­graines in­clude trip­tans and opi­oids (which have high ad­dic­tion po­ten­tial). Em­gal­ity, a more promis­ing treat­ment for epi­sodic cluster headaches, has re­cently en­tered the mar­ket, but its long-term risk pro­file and effi­cacy have not yet been es­tab­lished.

  • Bob Wold founded “Cluster Busters” in 2002 with the ex­plicit pur­pose of try­ing to get psychedelics to be pre­scrip­tion med­i­ca­tion (see his lec­ture Treat­ing Cluster Headaches with Psychedelics). He tried over 75 differ­ent pre­scrip­tion med­i­ca­tions and was at the end of the rope when he found psychedelics could be helpful:


As noted in this Qualia Com­put­ing ar­ti­cle, the sur­vey sur­faced that about 83% of all cluster headaches are ex­pe­rienced by 20% of the suffer­ers, most of which are clas­sified as ‘chronic’. No ex­ist­ing med­i­ca­tion has been ap­proved for use to treat chronic cluster headaches. Va­por­iz­ing DMT could be the first such treat­ment, offer­ing in­stant re­lief for cluster headaches as of­ten as they arise in a (po­ten­tially large) per­centage of suffer­ers.

II. Solu­tion:

“One of the most in­cred­ible ex­pe­riences of my life was when I first aborted a CH [cluster headache] with DMT. That feel­ing of go­ing from a place of ex­cru­ci­at­ing pain…and feel­ing the pain fiz­zle away and die in a mat­ter of sec­onds” (source)

It is known by a ma­jor­ity of cluster headache suffer­ers that psychedelics can be highly effec­tive treat­ments. Due to the le­gal sta­tus of psychedelics, no ran­dom­ized con­trol­led trial (RCT) has been con­ducted, but anal­y­sis has been done on on­line fo­rum re­sponses and anony­mous sur­veys, and in­ter­views have been recorded. Ev­i­dence from these re­ports points to a num­ber of im­por­tant fac­tors: tryptamines (the class of psychedelics which in­cludes com­pounds like N,N-DMT and psilo­cy­bin, the ac­tive chem­i­cal in ‘magic mush­rooms’) seem es­pe­cially effec­tive, sub-psy­choac­tive and non-psychedelic doses can be ther­a­peu­tic, and psychedelics can also de­crease the fre­quency of headaches on long time hori­zons. While smok­ing/​va­por­iz­ing is the fastest method of ad­minis­tra­tion available, in­for­ma­tion from a pri­vate cor­re­spon­dence sug­gests that the FDA may be averse to ap­prov­ing in­halants. In­tra­mus­cu­lar ad­minis­tra­tion, uti­liz­ing Rick Strass­man’s pro­to­col, could be an al­ter­na­tive that would achieve rapid re­lief with­out the use of an in­hala­tion de­vice[2]. Since the pain be­ing ex­pe­rienced is so se­vere, hav­ing a faster method of ad­minis­tra­tion is crit­i­cal.

From the rele­vant aca­demic liter­a­ture:

  • “The in­doleamine hal­lu­cino­gens, psilo­cy­bin, ly­ser­gic acid diethy­lamide, and ly­ser­gic acid amide, were com­pa­rable to or more effi­ca­cious than most con­ven­tional med­i­ca­tions. Th­ese agents were also per­ceived to shorten/​abort a cluster pe­riod and bring chronic cluster headache into re­mis­sion more so than con­ven­tional med­i­ca­tions.” (source)

  • “Also, for DMT, it was sug­gested that sin­gu­lar or in­fre­quent dosage could have po­ten­tial long-term benefi­cial effects on headache di­s­or­ders: ‘Even a sin­gle dose, or per­haps a cou­ple, can be a lifelong benefit.’” (source)

  • “Of in­ter­est, an open-la­bel study found that similar com­pounds (2-bromo-LSD) with­out psychedelic effect were promis­ing for this pur­pose” (source)

From on­line sur­veys:

  • A sur­vey of mem­bers of on­line cluster headache fo­rums re­vealed that 68% of re­spon­dents who used tryptamines had a 4 or 5 out of 5 re­lief. 5 in­di­cates “com­pletely elimi­nated the cluster headaches”.

  • This sur­vey again sug­gests that the main bar­rier to use is lack of ac­cess and hal­lu­cino­genic effects. As we found in an in­ter­view with an anony­mous sufferer (see be­low), hal­lu­cino­genic effects may be avoid­able.


Difficulty get­ting. 0 – Ex­tremely easy to ac­quire, 5 – Nearly im­pos­si­ble to acquire

Le­gal risk. 0 – Not con­cerned at all, 5 – Ex­tremely concerned


Side effects. 0 – Not con­cerned at all, 5 – Ex­tremely concerned

From in­ter­views with cluster headache suffer­ers who have tried N,N-DMT:

III. Philan­thropic Op­por­tu­ni­ties:

Due to the Sched­ule I sta­tus of psychedelics in the United States, pur­su­ing this in­ter­ven­tion in the US will not be fea­si­ble for a num­ber of years (see Sec­tion IV for more in­for­ma­tion on pur­su­ing FDA ap­proval for DMT for cluster headaches/​mi­graines).

A pos­si­ble solu­tion would be to cre­ate an on­line ed­u­ca­tion cam­paign pub­li­ciz­ing the re­sults of this re­port to cluster headache suffer­ers, des­ig­nated as ‘in­for­ma­tion-only’, and pur­su­ing the use of psychedelics to treat cluster headaches and mi­graines in coun­tries where tryptamines are le­gal, in­clud­ing Brazil, Ja­maica and the Nether­lands. In ad­di­tion, given the grav­ity of the di­s­or­der, it could be cost-effec­tive to fly pa­tients to such coun­tries for months at a time.

While we be­lieve that tra­di­tional met­rics such as the QALY do not ac­cu­rately cap­ture the suffer­ing caused by a cluster headache (see up­com­ing post on the true pain/​plea­sure scale), a rough QALY calcu­la­tion would be as fol­lows (fo­cus­ing on chronic cluster headache suffer­ers rather than av­er­age, since they com­pro­mise up to 83% of to­tal headaches[3]):

  1. Face­book AD cam­paign:

    1. An es­ti­mated 370,000 Amer­i­cans suffer from cluster headaches, 68% of whom are on Face­book[4] (=251,000). About 15% of these suffer from chronic cluster headaches (=37,740). Ac­cord­ing to Sprout So­cial, the av­er­age es­ti­mated cost per click of an ad cam­paign is $1.72. As­sum­ing 110 who click are cluster headache suffer­ers, to reach all chronic suffer­ers would take (bal­l­park) $650,000.

    2. As­sum­ing about 30% of those who view the ad will pur­sue the treat­ment (rough es­ti­mate-those who put 2 or less on sur­vey re­sults for ques­tions of le­gal­ity, difficulty to ac­quire etc.) and that in 68% of cases it cured or nearly cured their clusters (based on sur­vey re­sults), then the re­sult­ing in­crease in QALYs would be (37,740 peo­ple * 0.3 * 0.68) * [0.760 (QALY co­effi­cient) * 1 QALY – ( −0.429 (QALY co­effi­cient)* (0.47QALY)) [5]] = $650,000/​7, 404QALY = $87.70 per QALY.

    3. Th­ese ads could also be tar­geted to users in coun­tries where psilo­cy­bin and DMTare le­gal for use recre­ation­ally, in­creas­ing con­ver­sion rate. Fur­ther tar­get­ing could be done on Face­book groups (and other so­cial me­dia groups) which are as­so­ci­ated with cluster headache treat­ment.

IV. For-Profit Op­por­tu­ni­ties:

The re­cent emer­gence of psychedelics in for-profit busi­ness set­tings also af­fords the op­por­tu­nity for en­trepreneurs to seek le­gal reschedul­ing of N,N-DMT in the US for the pur­pose of treat­ing cluster headaches and/​or mi­graines. Below is an out­line of the pro­cess of nav­i­gat­ing the FDA IND pro­cess, which could re­sult in a change in le­gal sta­tus:

Mar­ket:

‘Or­phan dis­ease’ sta­tus:

There are two main clas­sifi­ca­tions of cluster headaches, chronic and epi­sodic. Epi­sodic cluster headaches are char­ac­ter­ized by pe­ri­ods of headaches (up to 8 times per day) of a week to a full year, which re­mit for pe­ri­ods from a month up to a year. Chronic cluster headaches, on the other hand, ei­ther last for longer than a year or have re­mit­tance pe­ri­ods of less than a month[6]. A meta-anal­y­sis from the NIH es­ti­mates that cluster headaches af­fect 124100,000 in the U.S., mean­ing an es­ti­mated 370,000 peo­ple suffer from cluster headaches a year[7]. Of these, about 15%, or 60,000, suffer from chronic cluster headaches.

The FDA grants ‘or­phan dis­ease’ sta­tus to dis­eases which af­fect fewer than 200,000 per­sons in the U.S per year, and offers in­cen­tives to those pur­su­ing treat­ments through the FDA’s IND pro­cess for such dis­eases, such as longer pe­ri­ods of ex­clu­sivity (monopoly on drug man­u­fac­ture and sale) for the treat­ment af­ter ap­proval.

  • The global mar­ket for mi­graine drugs (which en­com­passes cluster headache drugs) in 2017 was $1.7 billion.

    • Health­care and lost pro­duc­tivity costs as­so­ci­ated with mi­graine are es­ti­mated to be as high as $36 billion an­nu­ally in the U.S. Cur­rent es­ti­mates of cluster headaches’ an­nual cost in the U.S. is ~$3.5 billion.

  • Share of market

    • 5 years af­ter launch (with FDA ap­proval, with a 5-year monopoly) – serve 20% of chronic mi­graine suffer­ers (800,000), serve 20% of cluster headache suffer­ers (40,000)

      • Plat­form’s av­er­age an­nual rev­enue per pa­tient (mi­graines): $452/​pa­tient/​year

        • DMT Vape Pen – $20

        • 1g of DMT is ~$100, ap­prox­i­mately 50 doses (al­though an anec­dote in­di­cate 3mg may be suffi­cient). Com­pare to trip­tans, at ~$115 per 9 doses. As­sum­ing 20% markup:

          • Chronic mi­graines at 20mg doses: $120/​g*0.02g/​dose*15 doses/​month *12 months = $432/​pa­tient/​year.

      • Plat­form’s av­er­age an­nual rev­enue per pa­tient (cluster headache): $344/​pa­tient/​year-low es­ti­mate, $6932/​pa­tient/​year – high estimate

        • DMT Vape Pen – $20

        • There is sig­nifi­cant var­i­ance in fre­quency of cluster headaches: es­ti­mates range from [$120/​g*0.02g/​dose*30 doses/​month *3 months = $324, $120/​g*0.02g/​dose*120 doses/​month*12 months = $6912/​pa­tient/​year].

      • An­nual rev­enue, 5 years af­ter launch: $13.6M [low cluster headache es­ti­mate] – $344M [high cluster headache es­ti­mate]

      • An­nual rev­enue, 5 years af­ter launch (mi­graines): $344M

    • The 5-year (or more, if ‘or­phan dis­ease’ sta­tus is gained) monopoly pro­vided by the FDA would al­low for fur­ther R&D, and as-yet un­de­ter­mined pro­jects. Some promis­ing di­rec­tions:

Why now?

  • FDA on track to ap­prove MDMA ther­apy in 2021, psilo­cy­bin ther­apy in 2022

    1. FDA ap­proval will cat­alyze a large in­crease in de­mand for psychedelic services

    2. There is suffi­cient ev­i­dence to at­tempt bring­ing DMT for headaches through the FDA pro­cess as it be­comes in­creas­ingly open to psychedelic interventions

  • Rea­sons to start be­fore FDA ap­proval of MDMA and psilo­cy­bin:

    1. A “psychedelic re­nais­sance” is un­der­way: fund­ing for psychedelic re­search has sky­rock­eted, and mul­ti­ple psychedelic de­crim­i­nal­iza­tion ini­ti­a­tives (1, 2) have re­cently passed. Rid­ing the cur­rent wave of ac­tivist and pub­lic sup­port is ad­van­ta­geous to our efforts.

    2. More time to build re­la­tion­ship with the FDA (im­por­tant for seek­ing DMT clear­ance)

    3. More time to build re­la­tion­ships with or­ga­ni­za­tions cur­rently seek­ing FDA ap­proval for ther­a­peu­tic uses of psychedelics (MAPS & Com­pass Path­ways)

Challenges:

Reg­u­la­tory:

  • Tak­ing on the FDA IND pro­cess can be challeng­ing and high risk from an in­vest­ment stand­point. The av­er­age cost of suc­cess­fully com­plet­ing Phase 1-3 tri­als (af­ter which the drug can be resched­uled and ap­proved for med­i­cal use) is $100m, re­quires about 9-11 years and has a 6.7% suc­cess rate (pri­vate cor­re­spon­dence).

    • The Mul­tidis­ci­plinary As­so­ci­a­tion for Psychedelic Stud­ies (MAPS) has re­cently raised $26.7M for Phase 3 MDMA tri­als alone[8]. To­tal, MAPS has spent in the bal­l­park of $30M. If Phase 3 tri­als demon­strate statis­ti­cally-sig­nifi­cant re­sults, MDMA could be se­lec­tively resched­uled for use in ther­a­peu­tic set­tings, but would re­quire sub­se­quent Phase 4 tri­als.

  • The FDA is risk-averse and has in­curred back­lash from their last no­table reschedul­ing of fen­tanyl in 1985[9]. Con­vinc­ing the FDA to pur­sue reschedul­ing for treat­ment of a rel­a­tively rare dis­ease with other available med­i­ca­tions will likely be difficult.

  • The suc­cess or failure of MAPS in re­ceiv­ing ap­proval for MDMA will be cru­cial for defin­ing the reg­u­la­tory land­scape for other psychedelics. Should they fail, bring­ing an­other similar sub­stance through the pro­cess may prove much more difficult.

Com­pe­ti­tion:

  • As dis­cussed in Sec­tion I, most available mi­graine and cluster headache drugs are in­effec­tive, ex­pen­sive, and/​or have heavy risk pro­files. Em­gal­ity, a new mi­graine drug ap­proved last month, has re­ceived FDA ‘break­through ther­apy’ sta­tus for its abil­ity to de­crease the fre­quency of epi­sodic cluster headaches and has shown promise as a pal­li­a­tive for mi­graines as well[10]. Em­gal­ity has not been ap­proved for use in treat­ing chronic cluster headaches, how­ever, and does not achieve the same ra­pidity of ad­minis­tra­tion as the DMT vape pen (see Sec­tion III). Thus, our solu­tion is still crit­i­cal for re­liev­ing symp­toms in­stantly, and main­tains the ad­van­tage of be­ing el­i­gible to treat chronic cluster headaches, an ‘or­phan dis­ease’.

Busi­ness model:

  • We would de­sign stud­ies to fulfill the three-step FDA drug re­view pro­cess:

    1. Phase 1 stud­ies (typ­i­cally in­volve 20 to 80 peo­ple).

    2. Phase 2 stud­ies (typ­i­cally in­volve a few dozen to about 300 peo­ple).

    3. Phase 3 stud­ies (typ­i­cally in­volve sev­eral hun­dred to about 3,000 peo­ple).

Use of Funds

  • Ex­penses for re­search and op­er­a­tions staff

    • Tech­ni­ci­ans

    • Anal­y­sis consultants

    • Re­searchers with clini­cal experience

    • Le­gal coun­sel (pa­per­work)

  • Phase 1 FDA trial (our con­nec­tions to ex­per­tise in the field would re­duce the cost com­pared to av­er­age Phase 1 tri­als)

Data on Cost of Trials

The fol­low­ing in­for­ma­tion is from the MDMA/​PTSD Tri­als led by MAPS. How­ever, the treat­ment for PTSD in­volves: mul­ti­ple ther­apy ses­sions and an MDMA-trained psy­chother­a­pist. Ther­apy ses­sions also last 6-8 hours. Pre­sum­ably, some of these costs would not ap­ply to a DMT/​CH trial, so we ex­pect tri­als for DMT/​CH to be cheaper than the MDMA/​PTSD Tri­als.

How­ever, cluster headaches are not well suited to the ther­a­peu­tic en­vi­ron­ment that is used to treat men­tal health con­di­tions (they arise un­pre­dictably, and re­quire in­stant re­lief). This means there are likely sig­nifi­cant cost-sav­ing op­por­tu­ni­ties in the ex­per­i­men­tal de­sign pro­to­col.

Sum­mary of costs for MAPS IND Pro­cess:



[1] As­sume a world pop­u­la­tion of 7.7 billion peo­ple, and 53 out of 100,000 yearly prevalence suffer­ing from this. Go­ing by pub­lic health records, we see that the av­er­age num­ber of cluster headache at­tacks that a sufferer ex­pe­riences is about 30 a year (with a huge var­i­ance, where some peo­ple get only about 5 a year and some get them mul­ti­ple times a day). At­tacks last on av­er­age 1 hour (but range from 20 min­utes to 3 hours). Hence, the num­ber of peo­ple cur­rently ex­pe­rienc­ing a CH is: 0.00053*7,700,000,000*(30/​(24*365)) = 13,976.03 ~= 14 thousand

[2] Per­spec­tives on DMT Research

[3] Ac­cord­ing to survey

[4] https://​​www.face­book.com/​​busi­ness/​​help/​​1461718327429941

[5] For chronic suffer­ers, an av­er­age of be­tween 1-8 CH per day, 1-4 hours per CH, for ~0.47 years/​year hav­ing CH

[6] https://​​www.may­oclinic.org/​​dis­eases-con­di­tions/​​cluster-headache/​​symp­toms-causes/​​syc-20352080

[7] https://​​www.ncbi.nlm.nih.gov/​​pubmed/​​18422717

[8] https://​​maps.org/​​re­search/​​mdma/​​ptsd/​​phase3/​​timeline

[9] https://​​www.deadi­ver­sion.us­doj.gov/​​sched­ules/​​or­ange­book/​​or­ange­book.pdf

[10] https://​​in­vestor.lilly.com/​​news-re­leases/​​news-re­lease-de­tails/​​fda-ap­proves-em­gal­i­tyr-gal­canezumab-gnlm-first-and-only

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