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

by Quintin Frerichs

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. 
no_use_cluster_headache_difficulty_acquiring

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

no_use_cluster_headache_legal_concern

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

no_use_cluster_headache_side_effect_concern

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 1/10 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 DMT are 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 Size:

‘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 124/100,000 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
        • Tryptapens – $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
        • Tryptapen – $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:

Screen Shot 2019-06-06 at 12.34.09 AM


[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

Cluster Headache Frequency Follows a Long-Tail Distribution

[Warning: Disturbing content ahead. Why talk about it? This is an ethically very serious topic and it deserves more attention. But please beware that thinking about this might be bad for one’s mental health.]


One of the key insights that shows why Effective Altruism is so important is that the positive effect on the world that results from donating to various charities follows a long-tail distribution:

health interventionsCost-effectiveness of health interventions as found in the Disease Controls Priorities Project 2. See “The moral imperative towards cost-effectiveness in global health” by Toby Ord for more explanation. [Taken from: The world’s biggest problems and why they’re not what first comes to mind]

It is for this, among other, reasons why focusing on the best interventions really pays off. Where else can we expect long-tails to appear?


In Get-Out-Of-Hell-Free Necklace we discussed how introducing a new metric into the Effective Altruist ecosystem could shed light on neglected cost-effective interventions. We presented the Hell-Index:

A country’s Hell-Index could be defined as the yearly total of people-seconds in pain and suffering that are at or above 20 in the McGill Pain Index (or equivalent)*. This index captures the intuition that intense suffering can be in some ways qualitatively different and more serious than lesser suffering in a way that isn’t really captured by a linear pain scale.

In a future article we will discuss how the quality of suffering as a function of different medical and psychological conditions very likely follows a long-tail distribution. That is, some conditions such as Cluster Headaches (which affect about 1 in 1000 people worldwide) produce pain that is orders of magnitude worse than the pain experienced in other kinds of medical conditions, such as migraines (which are themselves already described as orders of magnitude worse than tension headaches). In other words, a 0-10 pain-scale is better thought of as a logarithmic compression of the true levels of pain rather than a linear scale. So concentrating on the worst conditions could really pay off for reducing suffering in bulk amounts.

Now: the long-tailed nature of suffering may extend beyond the quality of suffering, and show up also in its quantity. That is, the frequency with which people experience episodes of intense suffering, even among those who experience the same kind of suffering, is unlikely to be normally distributed.

Intuitively, one may think that how much suffering people endure on a given year follows a normal distribution. This intuition says that if the median number of hell-seconds people endure in a year is, say, 1,000, then people who are at the 90% percentile of hell-seconds experienced per year will be experiencing something like 1,500 or at most 2,000. If suffering follows a long-tail distribution, in reality the 90% percentile might be experiencing something more akin to 10,000 hell-seconds per year, the 99% percentile something akin to 100,000, and the 99.9% something akin to 1,000,000. If true, such a heavy skew of the distribution would suggest that we should concentrate our energies on addressing the problems of the people who are unlucky to be on the upper ranges, rather than be overly concerned with “the typical person”*.

Unfortunately, I come to share the bad news that suffering probably follows a very long-tail distribution:

It is generally acknowledged that Cluster Headaches are some of the most painful experiences that people endure. Having a single Cluster Headache, lasting anywhere between 15 minutes to 4 hours, is already an ethically unacceptable situation that should never happen to begin with. It is disheartening to know that 1 in 1,000 people experience such extreme pain. But the truth of the matter is yet much worse than we intuitively think…

We recently analyzed a survey** of Cluster Headache patients that was conducted with the intention of determining the reasons why sufferers do or do not use psychedelics to relieve their pain. As it turns out, LSD, psilocybin, and DMT all get rid of Cluster Headaches in a majority of sufferers. Given the safety profile of these agents, it is insane to think that there are millions of people suffering needlessly from this condition who could be nearly-instantly cured with something as simple as growing and eating some magic mushrooms.

We will get back to this in more depth in later articles, but for the time being what we want to highlight is the responses to the question “About how many cluster headaches do you get in a typical year?”.

After cleaning the data***, we end up with 270 participants. We then ranked the values from smallest to largest, and visualize them:

270_ranked

Honestly I am a bit suspicious of the very top numbers (I do not know how you can fit 25,000 Cluster Headaches in a year, so perhaps the participant interpreted the question as “lifetime number of Cluster Headaches”). So, just to be safe, we cut the top 20 highest numbers and visualize the bottom 250 values:

first_250_

This is clearly a long-tail distribution. And since many people online do claim to have 3 or more Cluster Headaches a day, I am inclined to believe this curve. To zoom in on some parts of the distribution, here are some additional histograms that focus on the lower percentiles:

If we take the logarithm of the number of yearly Cluster Headaches, the distribution looks remarkably normal:

log_of_estimated_total_half_bins_till_12

Natural log of the responses to the question “About how many cluster headaches do you get in a typical year?”

Using a Shapiro-Wilk normalcy test does not rule out a Gaussian distribution (p >0.05). Although this in no way shows that that the distribution is log-normal (which would require more specialized statistical analysis), it is at least suggestive of it.

I should also point out that the distribution is really close to the 80/20 Pareto principle – we see that the top 20% of the participants contain about 83% of the CH incidents per year. Below you will find the percent of the total number of incidents accounted for by the bottom x% of the respondents:

  1. The bottom 10% accounts for .06% of incidents
  2. The bottom 20% accounts for 0.36% of incidents
  3. The bottom 30% accounts for .95% of incidents
  4. The bottom 40% accounts for 1.82% of incidents
  5. The bottom 50% accounts for 3.17% of incidents
  6. The bottom 60% accounts for 5.54% of incidents
  7. The bottom 70% accounts for 9.56% of incidents
  8. The bottom 80% accounts for 17% of incidents
  9. The bottom 90% accounts for 30% of incidents
  10. The bottom 95% accounts for 43% of incidents

Below we also include the number of yearly Cluster Headaches experiences at different percentiles:

  1. 10% percentile experiences 5 CH/year
  2. 20% percentile experiences 17 CH/year
  3. 30% percentile experiences 30 CH/year
  4. 40% percentile experiences 45 CH/year
  5. 50% percentile experiences 70 CH/year
  6. 60% percentile experiences 105 CH/year
  7. 70% percentile experiences 200 CH/year
  8. 80% percentile experiences 365 CH/year
  9. 90% percentile experiences 730 CH/year
  10. 95% percentile experiences 1095 CH/year
  11. 98% percentile experiences 2190 CH/year

I believe that this information is crucial to consider when assessing cost-effective interventions to help people who endure intense suffering.


Here are some additional results from the survey.

cluster_headache_tryptamine_use

The following graphs are about the beliefs and attitudes of Cluster Headache sufferers who do not use tryptamines (LSD, psilocybin, DMT, etc.) to treat their condition:

 

I think it is fair to say that the survey shows that one of the biggest barriers preventing CH patients from using tryptamines to treat their condition is simply the difficulty of acquiring them. Since a number of interviews we’ve conducted have shown that even sub-hallucinogenic doses of DMT can abort cluster headaches (writeup coming soon), more education could easily address the barrier of being concerned about hallucinogenic side effects. The social stigma seems like a minor problem, and the legal implications (the hardest to change, perhaps), are a big concern to about half of the participants (ratings of 4 or 5/5). Hence the importance of passing new laws allowing people with this condition to use them without repercussions.

Do CH sufferers who do not use tryptamines think they would work?

no_use_cluster_headache_belief_in_effectiveness

And do they work? Here is what the CH sufferers who do use them say:

use_cluster_headache_effective

Effectiveness

use_cluster_headache_kind

Tryptamines used

If we interpret a 2 or 3 in the 0 to 5 scale as an equivalent to a “maybe”, and a 4 or 5 as a “yes” to the question “do they work?” we see a big difference between non-users beliefs in their effectiveness and their reported effectiveness by users. 24% of people who use tryptamines to treat their CHs report that “They have completely eliminated the cluster headaches” and in total 68% mark it as either a 4 or a 5 in the scale (which we can interpret as “working” even if not “completely eliminating them”). This is compared to only 30% of non-users who believe the tryptamines would work. This large discrepancy also suggests that outreach and education could help sufferers give this approach a try.

Finally, we also looked at whether the users and non-users had different number of incidents per year (reasoning that perhaps those who experience more incidents would be more desperate to try legally and socially risky treatments). We notices that there is a very slight difference in the mean (and mean-log) for the number of CH incidents a year between the 20% of sufferers who treat their CHs with tryptamines and those who don’t. I won’t report the difference in the mean because the skew of the distribution makes such a metric deceptive, but the log-mean of yearly incidents of tryptamine users is 4.73 whereas for all the rest it is 4.10 (which reaches statistical significance of p < 0.05 based on a t-test). That said, we don’t think this is a very practically relevant difference. The distributions look roughly the same:

tryptamine_vs_non_tryptamine_users

The similarity between these two distributions also suggests that there is a long way to go to make sure that those who are the worse off get prompt access to tryptamines.

The End.


See also https://clusterbusters.org/, which is an organization that aims to make psychedelics legally available to people who suffer from this condition. Please consider donating to them to help this very important cause. Also consider donating to MAPS which is championing the use of psychedelics for mental health applications. Finally, consider also donating to organizations that care and strategize about how to reduce intense suffering, such as: QRI, FRIOPIS, and The Neuroethics Foundation.


*There are instrumental considerations here – if experiencing more than, say, 5,000 hell-seconds in a year is very likely to make you depressed and ineffective, then it might pay-off to also spend resources on keeping as many people as possible below that level. In particular, to be an effective Effective Altruist it pays off not to be heavily depressed and nihilistic.

**Thanks to Harlan Stewart for taking the initiative to conduct this survey. He advertised it on the Facebook groups and subreddits of Cluster Headache sufferers and got 371 responses.

***Some people provided numerical answers, which we used directly. Some other people provided ranges, in which case we used the middle point between the values provided (e.g. “200 to 300” was coded as “250”). Some people provided lower bounds, in which case we simply used such lower bound (e.g. “500+” was coded as “500”). We discarded the data of people who didn’t provide an answer in any of those formats – which left 270 participants. A more strict analysis that uses *only* the numerical responses results in the same observations listed above (e.g. the distribution is equally long-tailed and it appears to be log-normal).


[Cross-posted in Effective Altruism Forum]

Get-Out-Of-Hell-Free Necklace

An approach to doing good is to come up with a metric for what constitutes good or bad, and then trying to do things that will optimally increase or decrease such metric, as the case may be.

If you do this, you have to be careful about what metric you choose.

If you have an ontology where you measure good by “number of people who feel benefited by you”, you might end up doing things like sending everyone you can a doughnut with a signed note. If instead your metric is “number of people classified as poor” you might do best to focus on interventions that get people just over the hump of poverty as defined by your scale. And so on.

Conscientious and systematic altruists tend to see problems with metrics like those above. They realize that “people impressed” and “being poor according to an economic metric” are not metrics that really carve nature at its joints.

Dissatisfied with misleading metrics, one then tends to look closer at the world and arrive at metrics that take into account the length of different lives, their quality, their instrumental effect in the world, how much are they exactly being benefited by the intervention relative to other cost-effective alternatives, and so on. And that’s how you get things like Quality Adjusted Life-Years (QALY), micromorts, and the happiness index.

This is, I think, all moving in the right direction. Metrics that make an effort to carve nature at its joints can provide new lenses to see the world. And looking through those lenses tends to generate novel angles and approaches to do a lot of good.


earth-683436_960_720

This is why today I will suggest we consider a new metric: The Hell-Index.

A country’s Hell-Index could be defined as the yearly total of people-seconds in pain and suffering that are at or above 20 in the McGill Pain Index (or equivalent)*. This index captures the intuition that intense suffering can be in some ways qualitatively different and more serious than lesser suffering in a way that isn’t really captured by a linear pain scale.

What does this metric suggest we should do to make the world better? Here is an idea (told as if narrated from the future):


Between 2030 and 2050 it was very common for people to wear Get-Out-Of-Hell-Free Necklaces. People had an incredible variety of custom-fit aesthetic and practical additives to their necklaces. But in every single one of them, you could rest assured, you would find a couple of doses of each of these agents:

  1. N,N-DMT (in case of Cluster Headaches)
  2. Quetiapine (in case of severe acute psychosis)
  3. Benzocaine + menthol (for very painful stings)
  4. Ketamine (for severe suicidal feelings)
  5. Microdosed Ibogaine + cocktail of partial mu-opioid agonists (for acute severe physical pain and panic attack, e.g.. kidney stones)

Some other people would get additional things like:

  1. Beta blocker (to take right after a traumatic event)
  2. Agmatine (to take in case you suspect of having being brainwashed recently), and
  3. Caffeine (if you absolutely need to operate heavy machinery and you are sleep-deprived)

In all cases, the antidote needed would be administered as soon as requested by the wearer. And the wearer would request the antidote as indicated by a very short test done with an app to determine the need for it.

But why? What’s this all about?

The Get-Out-Of-Hell-Free Necklace contents were chosen based on a cost-benefit analysis for how to reduce the world’s Hell-Index as much as possible. Cluster-headaches, kidney stones, bad stings, severe psychotic episodes, suicidal depression, panic attacks, and many types of acute physical pain turned out to account for a surprisingly large percentage of each country’s Hell-Index. And in many of these cases, a substantial amount of the suffering was experienced before medical help could be able to arrive to the scene and do anything about it. A lot of that intense suffering happened to be tightly concentrated in acute episodes rather than in chronic problems (save for some notable examples). And by incredible luck, it turned out that there were simple antidotes to most of these states of agony, all of them small enough to fit in a single light necklace. So it was determined that subsidizing Get-Out-Of-Hell-Free Necklaces was a no-brainer as a cost-effective altruistic intervention.


By 2050 safe and cheap genetic vaccines against almost all of these unpleasant states of consciousness had been discovered. This, in turn, made the use of the Get-Out-Of-Hell-Free Necklaces unnecessary. But many who benefited from it- who had been unlucky enough to have needed it- kept it on for many years. The piece was thought of as a symbol to commemorate humanity’s progress in the destruction of hell. An achievement certainly worth celebrating.



* Admittedly, a more refined index would also distinguish between the intensity of different types of pain/suffering above 20 in the McGill Pain Index (or equivalent). Such index would try to integrate a fair “total amount of hellish qualia” by adding up the pain of each state weighted by its most likely “true intensity” as determined by a model, and then do so for each model you have and weight the contribution of each model by its likelihood. E.g. do both a quadratic and an exponential conversion of values in the 0 to 10 visual analogue scale into dolors per second, and then do a likelihood-weighted average to combine those results into a final value.

Low-Dose Ibogaine + Opioids: A Possible Treatment for Chronic Pain, Schizophrenia, and Depression?

Excerpt from Ibogaine in the 21st Century: Boosters, Tune-ups and Maintenance by Ibogaine treatment experts Patrick K. Kroupa and Hattie Wells


“Dirty” Maintenance

For some, abstinence from narcotic analgesics is not a reality-based goal. Many chronic pain patients are really not going to cast off their crutches [sic], light up some medical marijuana and dance in the meadow, after ibogaine.

In addition to chronic-pain patients, there are many people who are using narcotic analgesics to self-medicate a variety of comorbid conditions. In some cases a “successful” detox from opiates means that somebody can look forward to a lifetime’s worth of maintenance on neuroleptics.

Given the choice between opiates and neuroleptics, there is no simple answer, but the side-effects of current anti-psychotic medications can be devastating. When you compare the quality of someone’s life when they are controlling schizophrenia, for example, through the use of opiates (which tend to have extremely mild side effects) vs. the qualify of life attained using sanctioned medicines (usually neuroleptics, with Cogentin to alleviate some of the side-effects anti-psychotics produce), it is entirely possible, even probable, that the person is happier with the opiates.

Ibogaine is remarkably effective in addressing one of the primary problems in any sort of opiate or opioid maintenance: tolerance. Over time, individuals find they must do extremely high doses of their medications in order to achieve any effect whatsoever.

WARNING: the following category should be considered highly experimental. There is a complete lack of published scientific data regarding the following examples. The difference between 50mg and 500mg is extremely significant and quite possibly fatal. Ibogaine potentiates the analgesic effect of opiates and opioids.

Individual 1: Male, mid-30’s, in good health, who has experienced full-blown resets using ibogaine HCl in the past. His average daily intake was 20Mgs oxycodone and 4–6Mgs hydromorphone (Dilaudid), which he is prescribed for pain management.

By using a very low-dose regimen of 25–50Mgs of ibogaine HCl on a daily basis, he was able to taper down to a point at which 3.75Mg of oxycodone is subjectively providing him with identical pain relief.

He began by taking 25Mg ibogaine HCl per day, and was able to immediately halve his intake of narcotic analgesics with no withdrawal symptoms or discomfort whatsoever. After 6 days he increased the ibogaine HCl to 40Mg, and at week two, he went up to 50Mg a day of ibogaine HCl. After 22 days of ibogaine maintenance, he took a ten day break, before returning to 50Mg which he presently takes every other day. His intake of oxycodone has remained consistent at 3.75Mg/day.

In his own words, “The goal with adding ibogaine to the oxycodone is to minimize if not end the need for it [oxycodone] for pain management. The HCl seems to help with the pain, or at least gives me awareness to take better care of my body by stretching, drinking more water and to get outside for exercise and sunshine.

Most importantly the HCl has given me a feeling of well being and feeling comfortable in my place in the universe, allowing me to process through a depression I have been suffering from. I feel GREAT. The darkness has lifted, the impending doom is cast away! The low dose regimen has also been extremely helpful in musical inspiration; songs I had half-written are coming to completion and new songs are being created. There is a distinct connection between ibo and rhythm/melody, and further underscores for me the important aspect of music in the Bwiti ceremonies.

Individual 2: Female, early 40s, overall good health but suffering from anorexia, has been physically dependent on narcotic analgesics for 19 years. Her use started with heroin and eventually shifted to methadone maintenance and finally hydromorphone (Dilaudid). She has extreme fear and dislike of “tripping” and has repeatedly refused to take a full-blown ibogaine reset.

Her average daily intake was 28Mg of hydromorphone which she “cold-shakes” (breaks down the pills in a cooker so they can be injected) and IVs.

She began by doing 35Mg of ibogaine HCl and was immediately able to stop injecting the hydromorphone and obtained similar analgesia from 24Mg of Dilaudid. Over a period of five days she maintained on 35Mg of ibogaine HCl while continuously decreasing the hydromorphone, which she was taking orally, as prescribed. After five days she was on 16Mg of hydromorphone.

At the start of day 8 she began attending psychotherapy. Over the next two weeks she gradually increased her intake of ibogaine HCl to 50Mg/day, and decreased hydromorphone to 6Mg. On day 19, she took a 10 day break from ibogaine HCl, and her hydromorphone intake rose back to 12Mg/daily (oral), before tapering back down to 6Mg/day within hours of restarting ibogaine maintenance at 35Mg.

At six months out, this cycle appears to be consistent. She takes a break from ibogaine maintenance every 20 days. Slowly drifts from 6Mg/day of hydromorphone, up to 12Mg, before restarting ibogaine at 35Mg/day, at which point she drops back to 6Mg—which appears to be her comfort zone—while gradually increasing ibogaine HCl to 50Mg/day.

She has plans to try a 500Mg dose of ibogaine HCl, and attempt complete cessation of narcotic analgesics.


See also: Low-Dose Ibogaine for Hedonic Tone Augmentation, Anti-Tolerance Drugs, and On Hitting the Actual Target of Hedonic Tone for more up-to-date information.

An Infinite Variety of Waste

Excerpt from The Mating Mind: How Sexual Choice Shaped the Evolution of Human Nature (2000) by Geoffrey Miller (pg. 128-129)

Zahavi’s handicap principle and the idea of condition-dependence* are different perspectives on the same thing. The handicap idea emphasizes that sexual ornaments and courtship behaviors must be costly in order to be reliable fitness indicators. Their cost can take almost any form. They can increase risk from predators by making an animal more conspicuous with bright colors. They can increase risk from germs by impairing an animal’s immune system (which many sex hormones do). They can burn up vast amounts of time and energy, like bird song. They can demand a huge effort to obtain a small gift of meat, as in human tribal hunting.

As with Veblen’s conspicuous consumption principle, the form of the cost does not matter much. What matters is the prodigious waste. The waste is what keeps the fitness indicators honest. The wastefulness of courtship is what makes it romantic. The wasteful dancing, the wasteful gift-giving, the wasteful conversation, the wasteful laughter, the wasteful foreplay, the wasteful adventures. From the viewpoint of “survival of the fittest,” the waste looks mad and pointless and maladaptive. Human courtship even looks wasteful from the viewpoint of sexual selection for non-generic benefits, because, as we shall see, the act of love considered most romantic are often those that cost the giver the most, but that bring the smallest material benefits to the receiver. However, from the viewpoint of fitness indicator theory, this waste is the most efficient and reliable way to discover someone’s fitness. Where you see conspicuous waste in nature, sexual choice has often been at work.

Every sexual ornament in every sexually reproducing species could be viewed as a different style of waste. Male humpback whales waste their energies with half-hour-long, hundred-decibel songs that they repeat all day long during the breeding season. Male weaverbirds waste their time constructing ornamental nests. Male stag beetles waste the matter and energy from their food growing huge mandibles. Male elephant seals waste a thousand pounds of their fat per breeding season fighting other elephant seals. Male lions waste countless calories copulating thirty times a day with female lions before the females will conceive. Male humans waste their time and energy getting graduate degrees, writing books, playing sports, fighting other men, painting pictures, playing jazz, and founding religious cults. These may not be conscious sexual strategies, but the underlying motivations for “achievement” and “status”- even in preference to material sources- were probably shaped by sexual selection. (Of course, the wasteful displays that seemed attractive during courtship may no longer be valued if they persist after offspring arrive- there is a trade-off between parental responsibilities and conspicuous display.)

The handicap principle suggests that in each case, sexual selection cares much more about the prodigious magnitude of the waste than about its precise form. Once the decision-making mechanisms of sexual choice get their necessary information about fitness from a sexual display, everything else about the display is just a matter of taste. This interplay between waste and taste gives evolution a lot of elbow room. In fact, every species with sexual ornaments can be viewed as a different variety of sexually selected waste. Without so many varieties of sexual waste, our planet would not be the host of so many species.


* (from Glossary, pg. 437) Condition-dependence: A trait’s sensitivity to an animal’s health and energy level. For example, dance ability is condition-dependent because tired, sick animals can’t dance very well.

The Meaning Machine

Excerpt from Every Cradle Is a Grave: Rethinking the Ethics of Birth and Suicide (2014) by Sarah Perry

Suppose there were an experience machine that would give you any experience you desired. Superduper neuropsychologists could stimulate your brain so that you would think and feel you were writing a great novel, or making a friend, or reading an interesting book. All the time you would be floating in a tank, with electrodes attached to your brain. Should you plug into this machine for life, preprogramming your life’s experiences?

– Robert Nozick, Anarchy, State, and Utopia 

I believe that we should be very cautious about creating conscious beings, and I believe that the ideal number of conscious beings (and perhaps even living beings) in the universe is probably zero, for the good of those beings themselves.

Since suffering and misery are inescapable parts of life, if we are to justify creating life there must be something that outweighs suffering and misery within the space of universal judgements. Candidates generally fall into two categories. The first category is essentially hedonist: pleasure or good experiences are said to outnumber or outweigh bad experiences. This is the objection Bryan Caplan is making with his Free Disposal argument, discussed in the first chapter; assuming preferentism (that people choose what is good for them), and assuming that people have free choice in the relevant arenas, people would merely commit suicide if it were not true that the pleasure of life outweighs the suffering. And since only a million people per year commit suicide, creating life is obviously the right choice. A more subtle variation of this argument does not rely on suicide, but on a sort of imaginary survey: most people would probably report that their lives are worth living, that the good outweighs the bad, and therefore it must.

The second category of responses is that there is something valuable and meaningful about life that makes it worth living even if the bad vastly outweighs the good. In the previous chapter, we explored and categorized some of the things that people find meaningful, noting how these change according to circumstance and over time. One of the most salient features of the things that make life seem meaningful is that they frequently rely on illusion: the illusion of unchanging permanence, of a future state of happiness, of one’s ability to affect the world. It is my view that the sense of meaningfulness is itself an illusion, a cognitive phenomenon that is very adaptive for individuals and groups. This illusion is maintained by communities in order to organize the behavior of individuals, in part by easing their suffering.

One response to this is to counter that meaning is not an illusion- that there is real value in the world beyond what is experienced by living beings. Unfortunately, the proposed real and true meanings are often difficult to express in words to others who do not sense their truth. The feeling that life is meaningful is a pre-rational sensory perception that is widely shared. However, the specific meanings that people find satisfying and convincing are disparate and often contradictory. These underlying realities should make us question whether the sense that life is meaningful- or that some specific meaning can be found in life- is a true observation, or merely an illusion. The very adaptiveness of this belief, even if it were not true, must also make us suspect its veracity. The meaning realist has the further problem that no specific meaning is held by a majority of humanity; if there is one true meaning, then whatever it is, the majority of people’s lives go very badly because they do not perceive it.

Another response is that while meanings vary, it is enough that almost everyone finds some meaning in life. In other words, that sense that life is meaningful is enough to justify life, and the myriad meanings found and elaborated by individuals are all, in fact, the meaning of life. This seems to be the most common position articulated in modern post-Christian Western societies: if a person finds his life to be meaningful, then it is meaningful- even if different people find contradictory meanings in life. One person might find a sense of meaning in fighting for equality, another in ethno-nationalism, and they are both right.

This second response is actually a variation on hedonism, in that the experience of meaning, rather than the experience of pleasure, provides value. According to this view, a life of overwhelming suffering but with a deep experience of meaning might be better than a life of joy and pleasure that is internally felt to be meaningless. But ultimately, divorced from the meaning realism of the first response, this grounds meaning in subjective experience; the sense of meaning becomes another form of pleasure. The modern ideas that it is up to each individual to find meaning in life, and that this meaning justifies life, means accepting a meaning-based Experience Machine.

The things that we find to be meaningful are, in fact, miniature Experience Machines. They rely on illusion and filter the information that reaches us so that we may continue to feel that life is meaningful, or continue to search for meaning in life if it is missing. They are very useful; they help us organize our behavior, coordinate with others, and manage our emotions. In a practical sense they often make the suffering of life bearable; but, once they are recognized to be illusions, they cannot justify suffering in an abstract sense any more than pleasure can.

We need not jump into a Nozickian Experience Machine to get pleasure and a sense of meaning from intricate illusions. The Reverse Experience Machine experiment is close to the illusion we find ourselves in- if we found out we were in an Experience Machine already, would we choose to leave it for the real world? Institutions, religions, social communities, and even individual people function as Experience Machines, creating and maintaining illusions that help us feel that life is worthwhile. A meaning realist would reject the Experience Machine, but to be consistent he must also reject those aspects of life that use illusion or information filters to provide meaning. A meaning subjectivist has little ground to reject the Experience Machine. This has implications for the justification of life’s misery based on meaningfulness.


Excerpt from SUPERHAPPINESS: Ten Objections To Radical Mood-Enrichment by David Pearce

The ‘EXPERIENCE MACHINE’ objection [to engineering superhappiness with genetic technologies]

According to this objection, the prospect of “artificially” ratcheting up our hedonic set-point via biotech interventions just amounts to a version of Harvard University philosopher Robert Nozick’s hypothetical Experience Machine. Recall the short section of Anarchy, State, and Utopia (1974) where Nozick purportedly refutes ethical hedonism by asking us to imagine a utopian machine that can induce experiences of anything at all in its users at will. A full-blown Experience Machine will presumably provide superauthenticity too: its users might even congratulate themselves on having opted to remain plugged into the real world – having wisely rejected the blandishments of Experience Machine evangelists and their escapist fantasies. At any rate, given this hypothetical opportunity to witness all our dreams coming true, then most of us wouldn’t take it. Our rejection shows that we value far more than mere experiences. Sure, runs this objection, millennial neuroscience may be able to create experiences millions of times more wonderful than anything open to Darwinian minds. But so what? It’s mind-independent facts in the real world that matter – and matter in some sense to us – not false happiness.

POSSIBLE RESPONSE

This Objection isn’t fanciful. In future, technologies akin to Experience Machines will probably be technically feasible, perhaps combining immersive VR, neural nanobots and a rewiring of the pleasure centres. Such technologies may conceivably become widely available or even ubiquitous – though whether their global use could ever be sociologically and evolutionarily stable for a whole population is problematic. [If you do think Experience Machines may become ubiquitous, then you might wonder (shades of the Simulation Argument) whether statistically you’re most probably plugged into one already. This hypothesis is more compelling if you’re a life-loving optimist who thinks you’re living in the best of all possible worlds than if you’re a depressive Darwinian convinced you’re living in the unspeakably squalid basement.]

However, feasible or otherwise, Experience Machines aren’t the kind of hedonic engineering technology we’re discussing here. Genetically recalibrating our hedonic treadmill at progressively more exalted settings needn’t promote the growth of escapist fantasy worlds. Measured, incremental increase in normal hedonic tone can allow (post-)humans to engage with the world – and each other – no less intimately than before; and possibly more so. By contrast, it’s contemporary social anxiety disorders and clinical depression that are associated with behavioural suppression and withdrawal. Other things being equal, a progressively happier population will also be more socially involved – with each other and with consensus reality. At present, it’s notable that the happiest people tend to lead the fullest social lives; conversely, depressives tend to be lonely and socially isolated. Posthuman mental superhealth may indeed be inconceivably different from the world of the happiest beings alive today: meaning-saturated and vibrantly authentic to a degree we physiologically can’t imagine. Yet this wonderful outcome won’t be – or at least it needn’t be – explicable because our descendants are escapists plugged into Experience Machines, but instead because posthuman life is intrinsically wonderful.

Perhaps. The above response to the Experience Machine objection is simplistic. It oversimplifies the issues because for a whole range of phenomena, there is simply no mind-independent fact of the matter that could potentially justify Experience Machine-style objections – and deter the future use of Experience Machine-like technologies for fear of our losing touch with Reality. Compare, say, mathematical beauty with artistic beauty. If you are a mathematician, then you want not merely to experience the epiphany of solving an important equation or devising an elegant proof of a mathematical theorem. You also want that solution or proof to be really true in some deep platonic sense. But if you create, say, a sculpture or a painting, then its beauty (or conversely, its ugliness) is inescapably in the eye of the beholder; there is no mind-independent truth beyond the subjective response of one’s audience. For an aesthete who longs to experience phenomenal beauty, there simply isn’t any fact of the matter beyond the quality of experience itself. The beauty is no less real, and it certainly seems to be a fact of the world; but it is subjective. If so, then why not create the substrates of posthuman superbeauty rather than mere artistic prettiness?

There’s also a sense in which our brains already are (dysfunctional) Experience Machines. Consider dreaming. Should one take drugs to suppress REM sleep because our dreams aren’t true? Or when awake, should one’s enjoyment of a beautiful sunset be dimmed by the knowledge that secondary properties like colour are mind-dependent? [Quantum theory suggests that classical macroscopic “primary” properties as normally conceived are mind-dependent too; but that’s another story] If you had been born a monochromat who sees the world only in different shades of grey, then as a hard-nosed scientific rationalist, should you reject colour vision gene therapy on the grounds that phenomenal colours are fake – and grass isn’t intrinsically green? No, by common consent visual experience enriches us, even if, strictly speaking, we are creating reality rather than simulating and/or perceiving it. Or to give another example: what if neural enhancement technologies could controllably modify our aesthetic filters so we could see 80-year-old women as sexier than 20-year-old women? Is this perception false or inauthentic? Intuitively, perhaps so. But actually, the perception is no more or less authentic than seeing 20-year-old women of prime reproductive potential as sexier. Evolution has biased our existing perceptual filters in ways that maximised the inclusive fitness of our genes in the ancestral environment; but in future, we can optimise the well-being of their bodily vehicles (i.e. us). Gradients of well-being billions of times richer than anything humans experience are neither more nor less genuine than the greenness of grass (or the allure of Marilyn Monroe). Could such states become as common as grass? Again, I suspect so; but speculation is cheap.


Analysis

Sarah Perry argues that we already live in a meaning-based Experience Machine. David Pearce reminds us that our experience of the world is itself just a phenomenal representation of a mind-independent quantum mess, and that what makes us feel good or bad is merely a reflection of what increases or decreases the inclusive fitness of our genes. In both cases, Nozick’s Experience Machine thought-experiment is turned on its head. Namely, that if we value life, we are inescapably already agreeing to living on an Experience Machine of sorts.

You say: “I am not looking for happiness; I’m looking for meaning.” Well, the way in which your world-simulation is implemented is such that activities that foster the inclusive fitness of your genes feel good, while those that bring fewer future copies of your genes generally feel bad. Thanks to our neocortex, we are able to “encephalize” our deep primal emotions and render them in conjunction with (and indeed phenomenally embedded in) high-dimensional state spaces of consciousness. Key predictors of inclusive fitness such as social status, environmental stability, and the mutational load of one’s tribe are not explicitly rendered in our experience as “beneficial for your inclusive fitness.” Rather, they are rendered in a concrete simulation-congruent form (i.e. as meaningful), such as being a good person, having a home, and being able to tune in to highly evolved aesthetics, respectively. Indeed, we are adaptation executers rather than utility optimizers; the causal effect of our aesthetic preferences (e.g. preferring to think of ourselves as “meaning-seeking” rather than “pleasure-seeking”) is not legible from our subjective vintage point. But… the inherent entwining of meaning and valence (i.e. the pleasure-pain axis) is crystal clear as soon as we mess with one’s psychopharmacology, for people who fetishize meaning are not immune to mu-opioid antagonists. Unsurprisingly, it is hard to enjoy either a personal meaning, a sense of community, or even higher art while on the opioid-antagonist naltrexone. Likewise, isn’t it strange that psychedelics and empathogens seem to simultaneously increase depth of meaning and capacity for pleasure? Indeed, realizing that subjective meaning is implemented with valence gradients has extraordinary explanatory power. For this reason, it is thus clear that, as David Pearce likes to say, “if you take care of happiness, the meaning of life will take care of itself.”

What about anti-natalism? My take on anti-natalism is pretty standard for a negative leaning utilitarian and transhumanist. Namely, that selection pressures against any proclivity to self-limit human reproduction guarantees that the psychological traits that bring about hard anti-natalist views will not sustain themselves over time. If one impartially cares about the wellbeing of sentient beings, one should take into account how evolution works. Advocating for gradients of intelligent bliss rather than non-existence could satisfy anti-natalists’ craving for the absence of suffering while also being compatible with an understanding of the reality of selection pressures. Tongue-in-cheek, I thus advocate for antinatalists to have lots of children, and for pro-natalists to have no children at all. More seriously, the real solution is to develop and promote “Triple-S genetic counseling” so that every child that is born is emancipated from the agony of his or her- otherwise inevitable- future suffering.


See also: The Tyranny of the Intentional Object, Open Individualism and Antinatalism, The Purple Pill, and Consciousness vs. Pure Replicators

Frequency Specific Microcurrent for Kidney-Stone Pain

Excerpt from The Resonance Effect: How Frequency Specific Microcurrent is Changing Medicine (2017) by Carolyn McMakin 

Kidney Stone Pain

Everyone who has ever had a kidney stone will tell you that the kidney-stone pain is the worst. Emergency rooms treat it with morphine, and nothing else seems to touch it.

The phone rang on a summer Sunday morning and I hardly recognized the friend who grunted through gritted teeth to ask if “my machine” could treat kidney-stone pain. I told him that I’d never treated it before, but I’d be willing to try if he could make it to my house. He shuffled from the front door to the couch bent forward at the waist, sweating in pain. I put one wet graphite glove under his back and the other glove on his abdomen. He tried hard not to moan as I covered him with a soft blanket and placed my hand on top of the glove on his abdomen.

Education said that kidney-stone pain had to be about spasm in the ureter, the tube that carries the stone from the kidney to the bladder. The frequency for spasm was 29 hertz on channel A. The frequency for the ureter was 60 hertz on channel B. It did absolutely nothing: no warmth, no relaxation or softening, nothing. Maybe there was bleeding caused by the rough stone shredding the ureter as it traveled? I tried 18 hertz to stop bleeding on channel A. The glove didn’t get warm, and the pain didn’t change.

I really didn’t want my gray-faced friend to be my first failure. Reaching for inspiration, I tried the always-reliable 40 hertz to reduce inflammation. Nothing changed. Desperation amplified the small murmur of my intuition in my head, “Don’t get sloppy! Be thorough.”

There is a sequence of frequencies leading up to inflammation. The sequence was 20 hertz for “pressure or pain reaction,” 30 hertz for irritation, 40 hertz for inflammation. I never ran the whole sequence because 40 hertz always worked and I had no idea what a “pressure or pain reaction” might be. The buttons clicked down from 40 hertz to 20 hertz on channel A, and two things happened in seconds. The glove resting on his abdomen got hot — not just warm, it was hot. His abdomen started to soften. The feeling is hard to describe. It feels like a balloon feels when it has been sitting on the floor overnight. The tissue softens and stays soft while the correct frequency is working, and it returns to normal when the frequency is finished.

His voice was a little slurred when he fell asleep a few minutes later as he said, “Is that supposed to make me feel woozy?” His deep relaxed breathing said he was out of pain.

There are frequencies for the stone, so I tried those after twenty quiet minutes of watching him doze. The glove got hot, the abdomen softened, and ten minutes later he bolted awake and yelped, “The stone’s moving.” True to its promise, 20 hertz on A and 60 hertz on B reduced the pain again and put him back to sleep. Forty minutes later he left, pain-free, and passed the stone that night with no increase in pain.

I told this story at the Advanced Course in Australia a few weeks later, and one of the Australian practitioners reported that she treated her husband for kidney stone pain with 20 hertz on A and 60 hertz on B. He was out of pain in an hour and passed the stone uneventfully.

Every case of kidney stones treated since then has responded exactly the same way. When the patient has gripping lower back pain from lifting suitcases during a long dehydrating flight but treating the muscles doesn’t help, experience finally admits it’s not the muscle. Intuition says, “I wonder if it’s a kidney stone?” The learning curve is very steep and short when the glove gets hot, the muscles begin to relax, the pain goes down in minutes, and the patient falls asleep.

When one specific frequency combination, and only one, works every time anyone uses it, and when it does something that is otherwise impossible, then it can’t be impossible. It’s got to be resonance.

Every Child is a Genetic Experiment: FAAH Clinical Trials for Hedonic Recalibration as Educated Guesses Rather than Reckless Experimentation

by David Pearce, in response to Quora question: How do you break the hedonic treadmill?

 

The easiest pain to bear is someone else’s.
(François de La Rochefoucauld)

Could two small genetic tweaks get rid of most of the world’s mental and physical pain?
A tentative answer is: just conceivably. More cautiously, the problem of suffering should be genetically soluble this century. Before launching into a long list of caveats and complications – and outright scepticism – it’s worth considering a case study. The subject has waived anonymity.

Jo Cameron is a retired Scottish schoolteacher, a socially responsible vegan and pillar of the local community. Jo has gone though life in a perpetual state of “mild euphoria”. She has unusually high levels of anandamide (from the Sanskrit for “bliss”) and is never anxious, though her serenity may vary. Jo doesn’t feel pain, or at least not in any sense most of us would recognise: childbirth felt like “a tickle”. She is hyperthymic, but not manic. Unlike previously reported cases of congenital analgesia, Jo didn’t die young or find the need to adopt a “cotton-wool” existence to avoid bodily trauma. She came to the attention of medical researchers only when her disdain of painkillers for what “ought” to have been an excruciating medical procedure – a trapeziectomy on her right thumb – intrigued her doctor. “I had no idea until a few years ago there was anything that unusual about how little pain I feel – I just thought it was normal.
With CRISPR genome-editing, lifelong bliss could be normal.

Jo Cameron is first known case of someone with mutations in both the FAAH gene and its newly-discovered sister gene, FAAH-OUT, which modulates the FAAH gene. The FAAH gene (short for Fatty Acid Amide Hydrolase) is a protein-coding gene responsible for degrading bioactive fatty amides, most notably the endogenous cannabinoid anandamide. Previous mutations of FAAH are known, but the FAAH-OUT gene was previously reckoned a pseudogene. Single FAAH mutations are associated with high pain-tolerance, reduced anxiety and a sunny outlook without Jo’s “extreme” syndrome of well-being. Jo’s son has the single mutation.

Other case studies may be cited. I often use (again with prior consent) the example of my transhumanist colleague Anders Sandberg (“I do have a ridiculously high hedonic set-point”) – although Anders’ pain-sensitivity lies within the normal range. The pain-modulating SCN9A gene, which has dozens of alleles conferring varying pain (in)tolerance, is much better studied (cfHow much do our pain thresholds differ?).

What biologists call the Environment of Evolutionary Adaptation (EEA) ensures such outliers are rare. Although Jo Cameron shows accelerated wound-healing, not being a “normal”, neurotic mother on the African savannah would have carried a fitness-cost. Predators are unforgiving of relaxed moms. Our sugary “wildlife documentaries” barely hint at the cruelties of Nature. Pain, fear and anxiety are intimately linked. “Only the paranoid survive”, said Intel boss Andy Grove; and this bleak diagnosis can be true of market capitalism to this day. But we are not living on the African savannah – or even in a world of unfettered free markets. Looking ahead, all kinds of risks can be offloaded to artificial intelligence. AI and smart prostheses can potentially manage risks moreeffectively than bias-ridden humans. Intuitively, for sure, tampering with our reward circuitry will be hazardous. Genetically modifying or creating superhappy organisms with relative pain-insensitivity and enhanced zest for life will lead to increased personal risk-taking. Yet the story is more complicated. A great deal of risky and self-destructive behaviour in today’s world involves not happy, pain-free people, but the pain-ridden, depressive and psychologically disturbed. Life-loving optimists typically value life more – and seek to preserve and protect it. Anecdotally, I don’t think it’s a coincidence that some of the happiest people I know dedicate their lives to the study and prevention of existential risk.

So a practical question arises.
Should a large, well-controlled clinical trial of CRISPR babies be launched, with some babies carrying Jo’s two mutations, others a single FAAH mutation like her son, and controls?
If the trial is successful, then the controls and (in due course) the wider human population could enjoy remedial gene-therapy to share the benefits.

One of the few publications to recognise the far-reaching significance of Jo’s case is the magazine Wired (cfCrispr Gene Editing Could One Day Cut Away Human Pain). Instead of the double mutation promising “only” better drugs to treat pain, humanity can now tackle the problem of suffering at its source.

Bioconservative critics will be appalled at the idea: “Doctor Mengele!” “Eugenics!” “Designer babies!” “Gattaca!” “Brave New World!” Being malaise-ridden is normal and natural. Creating superbabies would be hubris. Where will it lead? How do we know gene-editing won’t be used by despots to create a race of fearless superwarriors?
In more measured language, how can experimentation with the lives of sentient beings without prior informed consent be ethically justified?

Indeed. Yet all babies born today are unique and untested genetic experiments. All baby-making entails creating involuntary suffering. None of our genetic experiments first passed muster with a medical ethics committee. Any proposal to create transhuman superbabies will probably strike our descendants as genetic remediation, not enhancement. If we reject the arguments of anti-natalists, who view Darwinian life as malware, then all prospective parents are committed to practising genetic experimentation – just not under that inflammatory label. So what’s at issue is not the principle of genetic innovation, only whether we should harness the new tools of CRISPR-Cas9 genome-editing to conduct our experiments more responsibly. If aspiring writers can benefit from proofreaders and editors, why not aspiring parents too – where the stakes are higher?

Your question asks about breaking the hedonic treadmill (cfWhat would people who never suffered be like?). Breaking or otherwise dismantling the hedonic treadmill is worth distinguishing from recalibration of its dial-settings. Hedonic adaptation can be broken in human and non-human animals by experimentally inducing “learned helplessness” and behavioural despair in response to chronic, uncontrollable stress. Hedonic adaptation can be broken at the other extreme by using intracranial self-stimulation of the mesolimbic dopamine system. “Wireheading” shows virtually no tolerance. Pathological cases of a broken hedonic treadmill occur “naturally” in chronic unipolar depression and, much more rarely, in euphoric unipolar mania. Attempts to cheat the hedonic treadmill via drugs are fraught with pitfalls. The most powerful mood-brighteners, namely the opioids, activate the hedonic treadmill rather than mitigate it. Some opioid users end up with a habit hundreds of times their starting dose. Natural selection did not design living organisms to be happy.

Functionally, therefore, genetic recalibration is a more fruitful strategy than abolishing the hedonic treadmill, both for the individual and society at large. For what it’s worth, I personally think we should aim for a hyperthymic civilisation built on a biology of invincible well-being. Future sentience will be underpinned by gradients of bliss. However, nothing so grandiose need be envisaged in order to warrant human CRISPR trials of happy babies. Grant some fairly modest ethical assumptions, e.g. other things being equal, intelligent moral agents should act so as to reduce the burden of suffering, or at least not wantonly add to it. For any genetic intervention that alters default hedonic tone, conserving information-sensitivity to “good” and “bad” stimuli is critical. In other words, we should aim to retain the hedonic treadmill but transform its negative feedback-mechanisms into a hedonistic treadmill – where “hedonism” is understood not in the amoral popular sense of a life of drink, drugs and debauchery, but as embracing Mill’s “higher pleasures”. Hence the hedonistic imperative. If clinical trials of superbabies go well, prospective parents world-wide could be offered the opportunity to have happy, heathy babies via CRISPR genome-editing, preimplantation genetic screening and counselling.

A biohappiness revolution would be extremely cost-effective. Depression, anxiety disorders and chronic pain-syndromes significantly reduce economic growth worldwide. By conserving hedonic adaptation, but ratcheting up hedonic range and hedonic set-points, humanity can conserve and enhance empathetic understanding, social responsibility and critical insight while enriching default quality of life. By conserving hedonic adaptation, we can also conserve cherished traditional values, if so desired. Yesterday’s utopias involved overriding the preferences of others, whether for their own notional good or in pursuit of some higher cause. By contrast, elevating your pain-tolerance and raising your hedonic set-point would radically enrich your life but wouldn’t challenge your values and preferences – unless one of your core values is preserving the genetic status quo.

What could go wrong with a biohappiness revolution?
Cue for vast treatises and a sci-fi movie.
However, as well as seriously – indeed exhaustively – researching everything that could conceivably go wrong, I think we should also invesigate what could goright. The world is racked by suffering. The hedonic treadmill might more aptly be called a dolorous treadmill. Hundreds of millions of people are currently depressed, pain-ridden or both. Hundreds of billions of non-human animals are suffering too. If we weren’t so inured to a world of pain and misery, then the biosphere would be reckoned in the throes of a global medical emergency. Thanks to breakthroughs in biotechnology, pain-thresholds, default anxiety levels, hedonic range and hedonic set-points are all now adjustable parameters in human and non-human animals alike. We are living in the final century of life on Earth in which suffering is biologically inevitable. As a society, we need an ethical debate about how much pain and misery we want to preserve and create.

Investing Time and Resources in Happiness

As a function of time and resources, what is the optimal way to reduce suffering and maximize happiness?

You have 1 minute and no money: Try to calm down and distract yourself with music.

You have 1 hour and 1 dollar: Ignore the dollar, just make a playlist of songs you really enjoyed in your life and play it as you dance.

You have 1 day and 50 dollars: Go get yourself some hard drugs.

You have 3 months and 1,000 dollars: Get some gym equipment, establish a workout routine, hangout with friends as much as possible, get laid, go to see movies, go to a beach.

You have 3 years and 3,000 dollars: Learn about Buddhist meditation, get fit, and then focus on achieving the Jhanas states. Stay in them for as long as you can.

You have 10 years and 10,000 dollars: Investigate charities that minimize suffering, or make your own. Fund-raise in order to eliminate suffering in people who have cluster-headaches by giving them access to tryptamine vape-pens, help the spread of pain-killers for people dying in hospitals in third-world countries, etc.

You have 50 years and 10,000,000 dollars: You found a research institute devoted to identifying the biochemical, functional, or behavioral causes of suffering, identify promising large-effect-size genetic modification technologies in order to enable sustainable hedonic-tone enhancement. You build a company that sells permanent hedonic tone amplification. With the money you get rid of factory farming and implement a wild-animal welfare system. Then you get rid of game-theoretical impasses using ultra-bliss technology.

On Hitting the Actual Target of Hedonic Tone

Practically speaking, I think that our single best psychopharmacological bet for tackling depression, anxiety, and above all chronic pain worldwide in the next decade is to:

1) Identify great, non-toxic, partial mu-opioid agonists with extremely high therapeutic index (e.g. tianepetine, 7-hydroxymitragynine, etc.), and

2) Prescribe them in conjunction with anti-tolerance drugs (such as proglumide, agmatine, black seed oil, small dose ibogaine, etc.).

I think that whomever manages to patent a mixture of partial opioid agonist + anti-tolerance drug that works in the long term will be a multi-billionaire within a couple of years while actually reducing/preventing massive amounts of untold suffering.

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Proglumide: A Promising Anti-Tolerance Agent (proof of concept of what is to come)


Ps. My core research at QRI is not pharmacological but rather phenomenological and “patternceutical“. So I am not pursuing the above line of research myself as the core objective of the next few years. But if I was looking into pharmacological options, that’s where I’d shine some light on. If you are in the field, I urge you to look into this option. For more info: “Anti-Tolerance Drugs“.