A presentation from 2021 to Karl Friston, world's most cited academic neuroscientist, most known for his landmark theory, the 'Free Energy Principle'. Dr. Friston's comments are excluded from the public version of the presentation. 

“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:

“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)

• “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)

• 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. 

• “If I’m starting to experience a CH and I vaporize as little as 3mgs [of DMT, sub psychoactive] I feel the pain subside almost completely within 3 to 5 seconds, and it doesn’t come back for a few days.” – (full document; also: another interview with an anonymous cluster headache sufferer)

1. Facebook AD campaign:
2. 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 1/10 who click are cluster headache sufferers, to reach all chronic sufferers would take (ballpark) $650,000.
3. 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.  
4. 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. 

• 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
• EDIT: A reader pointed out that my initial cost-effectiveness analysis linked a source for 1mg of N,N-DMT priced at ~$100, and my fermi estimate indicated that 1g of N,N-DMT priced at that rate, which significantly impacts the corresponding analysis. Another Sigma Aldrich quote of the price was ~$20/mg. I furthermore have significant uncertainty around up front cost of investment to bring N,N-DMT through Phase 1-3 clinical trials (based on estimates from private correspondence, the figure is in the $100M range) and the economies of scale which might result in drastically different price points for the substance. Further uncertainty comes from differences in regulation and cost of approval in other jurisdictions, particularly Canada and EU nations. For nations (such as Brazil) where N,N-DMT in the form of ayahuasca is fully legal, the cost may be far lower, but is very difficult to accurately estimate. For this post I will continue to quote the ~$20/mg figure from Sigma Aldrich, but given the at least 5X difference in price/dose based on sourcing country/company, I have low confidence in the quality and usefulness of the estimate.
• EDIT #2: Since the original posting, two large (public, private respectively) pharmaceutical companies, MindMed (https://mindmed.co/news/press-release/phase-2-clinical-trial-of-lsd-for-suicide-headaches-begins-treating-patients/) and BrightMindsBio (https://brightmindsbio.com/pain/, apparently partially inspired by this post!) have begun pursuing clinical trials of LSD and tryptamine-like agents for treating cluster headaches. Since these treatments can end a full cycle of cluster headaches rather than aborting a single headache, their cost-effectiveness may be higher, but I do not have the requisite information from these companies to evaluate the figures. I would still contend that, given the extreme nature of the pain caused by CH, an 'epipen-like' way to abort a headache at sub-hallucinogenic doses still seem ethically important and worthy of further study and examination. A Canadian-based pharmaceutical company has also begun developing GMP-grade N,N-DMT (https://www.baystreet.ca/articles/stockstowatch/62556/Entheon-Biomedical-Announces-DMT-Drug-Supply-Agreement-with-Psygen-Labs)
• 5 years after launch (with FDA approval, with a 5-year monopoly) – serving 20% of cluster headache sufferers (35,000 total in the US - rough estimate based on lifetime prevalence)
• Platform’s average annual revenue per patient (with 20% markup):
• Cost of DMT Vape Pen – $20
• 1mg of DMT cost is about $18, leading to ~$55/dose (anecdotal information indicates 3mg is sufficient). Compare to triptans, at ~$115 per 9 doses.
• There is significant variance in frequency of cluster headaches: estimates range from [$22 + $22/mg*3g/dose*30 doses/month *3 months = $5962/patient/year, $22 + $22/mg*3mg/dose*120 doses/month*12 months = $95,062/patient/year]. 10-15% of patients have chronic cluster headaches (https://en.wikipedia.org/wiki/Cluster_headache).
• Annual revenue estimate (10% chronic, 90% low-range episodic, 5 years after launch): $104M/year
• 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:
• Depression treatment ($13.7B market) 
• DMT may be beneficial for tobacco cessation ($7.0B market). 
• Ayahuasca shows significant evidence for efficacy in treating addiction. 
• There is anecdotal evidence that vaporized DMT is also effective in this space.

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: 

• 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. 

• 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

Crossposted to EA Forum: https://forum.effectivealtruism.org/posts/oqQCY5cgEtLCsXph8/using-ibogaine-to-create-friendlier-opioids

As the second in a series of two posts on how psychedelics can be beneficial to treating painful conditions:

Chronic Pain is a Massive, Debilitating Problem

“A new study by the CDC revealed that 50 million Americans (just under 20% of the age-adjusted adult population) suffered from chronic pain, which was defined as “pain on most days or every day in the past 6 months.” Nearly 20 million (about 7.5%) experienced high-impact chronic pain, defined as “limiting life or work activities on most days or every day in the past 6 months.”
– Who Is Hurting? The Prevalence Of Chronic Pain In America

Using IHME’s GBD visualization tool, about 5% of total DALYs come from conditions associated with chronic pain (back pain, neck pain and self-harm), not to mention the implications pain has in a variety of other conditions, from osteoporosis to cancer.

The Most Effective Tool for Pain Management Carries its Own Significant Burdens

Opioids  are highly effective as analgesics for managing chronic and acute pain, and are the most widely used pain treatment[1]. However, consistent use of opioids results in tolerance, dependence, withdrawal and overdose, which claimed the lives of 47,600 people in 2017[2]. Furthermore, the CDC estimates the total economic burden of prescription opioid misuse in the US is $78.5 billion a year, including the costs of health care, lost productivity, addiction treatment, and criminal justice involvement.[4]

Finding a solution for opioids’ dark side would help millions enjoy life, reduce the global health burden by no less than 5%, avoid 10s of thousands of future deaths, and recover billions in lost productivity.

A solution may be to combine variable doses of Ibogaine, the active compound found in the Tabernanthe iboga shrub with safer classes of opioids. 

The proliferation of opioids (specifically, full mu-opioid agonists) has this laundry list of problems: tolerance, addiction, withdrawal, overdose and euphoria (if one chooses to see it as a negative side-effect). In an effort to wean off of opioids, several groups have sought to attack these symptoms. Non-opioid therapeutics include cannabidiol (CBD) and CA-008, a TRPV-1 agonist which acts on nociceptive c-fibers in the peripheral nervous system similarly to capsaicin. These tend to be less habit-forming than opioids (attributed to their lower affinity for nuclei in the mesolimbic system), but also less effective at offering relief from intense neuropathic pain[4]. Other attempts to tame opioids have been made, most of them having the reduction of pleasure as the main target. CARA Therapeutics has created a kappa-opioid agonist which acts selectively on receptors in the peripheral nervous system to “produce little to no CNS-mediated side effects that one sees with traditional CNS-acting mu opioids like nausea/vomiting, sedation, respiratory depression, abuse, addiction or euphoria”. NKTR-181, a novel full mu-opioid agonist, is more direct: “NKTR-181, a first-in-class opioid analgesic, is a new chemical entity (NCE) that is the first full mu-opioid agonist molecule designed to provide potent pain relief without the high levels of euphoria that can lead to abuse and addiction with standard opioids”. As it turns out, addiction and pleasure have a complex relationship; one is not reducible to the other[5]. Euphoria-inducing psychedelic drugs and the jhana states of meditative absorption seem to lack the addictive profile of opioids. Pleasure and habit become decoupled over time in the path of opioid addiction as well, one fading with the other stubbornly immovable. If we can have opioids that forego tolerance, addiction, withdrawal and overdose, but keep the euphoria, wouldn’t that be better?

Ibogaine has a history of being used for the treatment of opioid addiction, but it may also have interesting properties for producing safer opioids as well. While at high doses (1g+) it creates intense psychedelic effects, it also has interesting properties at both lower doses of 500-600mg and at ‘microdoses’ of around 50mg. Ibogaine is illegal in many countries, but unregulated in Mexico, legal in Brazil, Gabon, and Costa Rica, and on the prescription drug list in New Zealand and Canada. For a more in-depth review of the history of Ibogaine and its use in treatment, read this review on Pysmposia. 

In this case study, a patient who had been a long-term opioid user and recently transitioned to methadone (a replacement for harder opioids like heroin, but maintaining the full agonist mu-opioid method of action) was taken off methadone without withdrawal using increasing doses of Ibogaine (150mg, 300mg, 400mg, 500mg, 600mg). As the Ibogaine dose was increased, the methadone was halved each time. We could allow opioid users to substantially decrease their opioid intake without withdrawal, while continuing to use opioids for pain management. After a few applications at the 100-600mg level, users could be maintaining their usage at ¼ of their original intake. Then they could utilize “dirty maintenance”: taking 25-50mg of Ibogaine daily while using a much lower amount of the opioid they typically use. Microdosing ibogaine alone is also potentially mood-enhancing, and some former opioid users have employed “clean maintenance” (i.e. just Ibogaine), to reduce post-acute-withdrawal syndrome (PAWS).

The reason these solutions work is because Ibogaine acts as an ‘anti-tolerance’ drug. It potentiates the effects of opioids and prevents patterns of tolerance and dependence from forming at the neurological level. When combined with full mu-opioid agonists, even in lower doses, this can pose a risk since the dose required to overdose could be more unpredictable with Ibogaine. A ‘best of both worlds’ solution would be to continue microdosing Ibogaine in conjunction with a partial mu-opioid agonist. Partial mu-opioid agonists prevent overdose by creating an upper-bound on activity at the opioid receptor and preventing the respiratory depression that causes death in full agonists.

While existing partial mu-opioid agonists, such as the drug combo of buprenorphine and naloxone are used in opioid replacement therapy settings, they too lack euphoria-producing properties. With this new class of analgesics, patients could choose when to start, stop, and for how long to take their pain medication without fear, along with a depression-preventing hedonic enhancement. For more, see: On Hitting the Actual Target of Hedonic Tone.

A well-known example of a partial mu-opioid agonist is 7-hydroxymitragynine, the active compound in kratom. Brazil is the only country to not prohibitively schedule either kratom or Ibogaine, and so might be an option for conducting research into this new form of non-tolerance-inducing opioid mixture. In the United States, research is being done at DemeRXfor approving Ibogaine through the FDA IND process for the detoxification of people afflicted with opioid addiction. Their success would also open the door to further innovation in Ibogaine-assisted pain treatments in the US.

Risks of Ibogaine

Unfortunately, Ibogaine has a harsher risk profile than most psychedelics, and has been associated with about 30 deaths due to cardiac complications. However, many researchers who have worked with Ibogaine for decades believe that these incidents can be minimized or even eliminated by standard medical practices like employing EKG screenings. Medical screenings should not only assess current heart health, but also in-system drugs, which can be potentiated by Ibogaine use, and can lead to unexpected overdose. In a population of drug users to be treated, higher incidences of poor heart health and the presence of other drugs likely contributed to a significant number of the cases of death recorded.

Mash et al. 2018 reviewed 191 cases of ibogaine therapy (all at Dr. Mash’s clinic on Saint Kitts) and found that there were no cases of cardiac-related death at doses used for interrupting addiction. Furthermore, Clear Sky Recovery has administered 1000s of Ibogaine sessions without a single fatality.

Iboga rescheduling in the US may be far off, but its potential shouldn’t be underestimated. As Hamilton Morris notes, Ibogaine is “alien technology”, with the potential to help us humans solve some of our greatest medical mysteries. For now, it’s enough to think that it might be able to a create stable, long-term pain medication with no risk of respiratory depression, tolerance, and minimal withdrawal. Along with risk-free… risk tolerant euphoria. Whether that sustainable euphoria will be available to all, remains to be seen.

[1] https://www.mayoclinic.org/chronic-pain-medication-decisions/art-20360371

[2] https://www.hhs.gov/opioids/about-the-epidemic/index.html

[3] https://www.moveforwardpt.com/resources/detail/7-staggering-statistics-about-america-s-opioid-epi

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920543/

[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782756/