Three Interesting Math Problems to Work on While on LSD

  1. Let P be a simple polygon with n>3 sides. A simple polygon is a polygon that does not self-intersect, but it is not necessarily convex. Prove that no matter the shape of P, there is always a diagonal (a segment that connects two vertices of P without intersecting any of its sides) that divides P into two polygons, both of which have at least n/3 sides.
  2. Let A and B be two points in the plane. Using only a compass and a straightedge, find the point C which is the exact middle point between A and B. Now do the same thing, but using only a compass.
  3. There are 17 point-sized light-houses in the plane. Assume that each of these lighthouses can shine light in any direction with an angle of 2*pi/17. Prove that no matter the position of each lighthouse, it is always possible to choose the angles at which they shine their light such that every point in the plane is illuminated (point-sized lighthouses don’t cast shadows).

In Selective Enhancement of Specific Capacities Through Psychedelic Training, Willis Harman and James Fadiman outline the results of a study about the potential use of psychedelics for problem solving. In the study, scientists, engineers, mathematicians, and designers took either 100 micrograms of LSD or 200mg of mescaline and worked on a problem they were personally invested in and which they had not been able to solve for at least 3 months. According to Fadiman, 9 out of 10 participants came up with a solution to the problem that was validated by the participant’s professional colleagues.

The three problems above are not easy, but they are also not insanely difficult. If it means anything to you, their level of difficulty might be around that of a problem 1 or 4 of an IMO, with the advantage that you do not need any fancy math to solve them (high-school math is more than sufficient). I do not know if solving these problems is easier or harder on psychedelics, but I figure I would share them as possible Schelling points for “challenging math problems to think about while on psychedelics” to see if anyone reports benefits from such a setup. I personally like these problems, and I can assure you that they do have interesting and clever solutions. Assuming you are already planning on taking a psychedelic substance in the future: I would recommend trying to solve one of these problems for at least 1 hour while sober, and then setting aside at least 30 minutes (preferably 1 hour) while on a psychedelic and giving it your full attention. Please let me know if you either solve the problem or get an interesting insight from such an exercise. I am particularly curious to hear about *what aspects* of the psychedelic state seemed to be either beneficial or detrimental in solving these problems. Even if you do not solve the problem, you may be able to think about it in new ways and derive useful insights. Again, if you do so, let me know as well.

Two Recent Presentations: (1) Hyperbolic Geometry of DMT Experiences, and (2) Harmonic Society

Here are two recent talks I gave. The first one is a talk about the Hyperbolic Geometry of DMT Experiences I gave at the Harvard Science of Psychedelics Club in mid-September (2019). And the second talk is about QRI‘s models of art, which took place in June (2019) at a QRI party in the Bay Area.


The Hyperbolic Geometry of DMT Experiences (@Harvard Science of Psychedelics Club)


Description

Andrés Gómez Emilsson from the Qualia Research Institute presents about the Hyperbolic Geometry of DMT Experiences.

At a high-level, this video presents an algorithmic reduction of DMT phenomenology which imports concepts from hyperbolic geometry and dynamic systems theory in order to explain the “weirder than weird” hallucinations one can have on this drug. Andrés describes what different levels of DMT intoxication feel like in light of a model in which experience has both variable geometric curvature and information content. The benefit of this model cashes out in a novel approach to design DMT experiences in order to maximize specific desired benefits.

See original article: The Hyperbolic Geometry of DMT Experiences: Symmetries, Sheets, and Saddled Scenes

And the Explain Like I’m 5 version: ELI5 “The Hyperbolic Geometry of DMT Experiences”

Presentation outline:

  • Thermometers of Experience
  • The Leaf Metaphor
  • Introduction to Hyperbolic Geometry
  • DMT Levels
  • Level 1: Threshold (& Symmetry Hotel)
  • Level 2: Chrysanthemum
  • Level 3: Magic Eye (& Crystal Worlds)
  • Level 4: Waiting Room
  • Level 5: Breakthrough
  • Level 6: Amnesia
  • Energy – Complexity Landscape
  • Dynamic Systems
  • Fixed Point
  • Limit Cycles
  • Chaos
  • Noise Driven Structures
  • Turbulence
  • Conclusion
  • Super-Shulgin Academy
  • Atman Retreat
  • Wrap-Up

About the speaker: Andrés studied Symbolic Systems at Stanford (and has a masters in Computational Psychology, also from Stanford). He has professional experience in data science engineering, machine learning, and affective science. His research at the Qualia Research Institute ranges from algorithm design, to psychedelic theory, to neurotechnology development, to mapping and studying the computational properties of consciousness. Andrés blogs at qualiacomputing.com.

The Qualia Research Institute (QRI) is a non-profit based in the Bay Area close to San Francisco which seeks to discover the computational properties of experience. QRI has a “full-stack approach” to the science of consciousness which incorporates philosophy of mind, neuroscience, and neurotechnology. For more information see: qualiaresearchinstitute.org

The Harvard Science of Psychedelics Club hosts events on psychedelic research, meditation, neuroscience, students sharing their own experiences, and much more.


Credits:

– Wallpaper group 632 rotating along each symmetry element – Nick Xu

– Many of the images are by Paul Nylander: http://bugman123.com/

– The Hyperbolic Honeycomb images and 3D prints are by Henry Segerman, who also has an awesome Youtube channel where he shows 3D printed math. We used his design to print the Honeycombs we were passing around during the lecture: https://www.youtube.com/user/henryseg

– Space-Time Dynamics in Video Feedback: Jim Crutchfield, Entropy Productions, Santa Cruz (1984): https://youtu.be/B4Kn3djJMCE

Many thanks to Andrew Zuckerman and Kenneth Shinozuka for helping organize this event. And thanks to David Pearce, Michael Johnson, Romeo Stevens, Quintin Frerichs, the anonymous trippers, and many others for making this work real.


And here are the slides:

 

Dynamic Systems animations:



Harmonic Society: 8 Models of Art for a Scientific Paradigm of Aesthetic Qualia


Description

Andrés Gómez Emilsson from the Qualia Research Institute gives a presentation about how art works according to modern neuroscience and philosophy of mind.

The video discusses eight different models of art: models 1 through 4 have been discussed in academic literature and the current intellectual zeitgeist, while models 5 through 8 are new, original, and the direct result of recent insights about consciousness as uncovered by modern neuroscience, philosophy of mind, and the work of the Qualia Research Institute.

Abstract:

We start by assuming that there are real stakes in art. This motivates the analysis of this subject matter, and it focuses where we place our gaze. We examine a total of eight models for “what art might be about”, divided into two groups. The first group of four are some of the most compelling contemporary models, which derive their strength from fields such as philosophy of language, economics, evolutionary psychology, and anthropology. These models are: (1) art as a word only definable in a family resemblance way with no necessary or sufficient features, (2) art as social signaling of desirable genetic characteristics, (3) art as Schelling point creation, and (4) art as the cultivation of sacred experiences. These four models, however enlightening, nonetheless only account for what David Marr might describe as the computational level of abstraction while leaving the algorithmic and implementation levels of abstraction unexamined. They explain what art is about in terms of why it exists and what its coarse effects are, but not the nature of its internal representations or its implementation. Hence we propose a second group of four models in order to get a “full-stack” view of art. These models are: (5) art as a tool for exploring the state-space of consciousness, (6) art as a method for changing the energy parameter of experience, (7) art as activities that induce neural annealing (which implements novel valence modulation, i.e. surprising pain/pleasure effects), and (8) art as an early prototype of a future affective language that will allow diverse states of consciousness to make sense of each other. These frameworks address how art interfaces with consciousness and how its key valuable features might be implemented neurologically. We conclude with a brief look at how embracing these new paradigms could, in principle, lead to the creation of a society free from suffering and interpersonal misunderstanding. Such a society, aka. Harmonic Society, would be designed with the effect of guaranteeing positive valence interactions using principles from a post-Galilean science of consciousness.

———————–

The 8 models of art are:

1. Art as family resemblance (Semantic Deflation)

2. Art as Signaling (Cool Kid Theory)

3. Art as Schelling-point creation (a few Hipster-theoretical considerations)

4. Art as cultivating sacred experiences (self-transcendence and highest values)

5. Art as exploring the state-space of consciousness (ϡ☀♘🏳️‍🌈♬♠ヅ)

6. Art as something that messes with the energy parameter of your mind (ꙮ)

7. Art as puzzling valence effects (emotional salience and annealing as key ingredients)

8. Art as a system of affective communication: a protolanguage to communicate information about worthwhile qualia (which culminates in Harmonic Society).


The presentation is based on an essay published in the Berlin-based art magazine Art Against Art (see: Issue #6).

Article is posted online here: Models 1 & 2, 3 & 4, 5 & 6, 7 & 8.


See more about the Qualia Research Institute at: https://www.qualiaresearchinstitute.org/

Andrés blogs at Qualia Computing: Top 10 Qualia Computing Articles


Infinite bliss!!!


And here are the slides:

Typical N,N-DMT Trip Progression According to an Anonymous Reader

I recently had the chance to interview someone who’s had 50+ vaporized N,N-DMT experiences. The person in question (who wishes to remain anonymous) is extremely smart, philosophically literate, and has a PhD in a STEM field from a top US university. Based on the interview notes I took, I wrote down what the progression of a “typical” experience looks like. The anonymous reader confirmed that this description provides an accurate account.


Progression for Waiting Room or Breakthrough-level DMT experiences (15-40mg range):

Onset stage (1-20 seconds): Psychedelic Molting – Sharpening of colors and edges, the world acquires a secondary layer (as if the world is “molting”), and then this second layer becomes unified and starts to resonate across the entire field of experience.pGIFjd3

Early come-up (20-40 seconds): The Hyper-Edge Capacitor – Visual field gets saturated with the Chrysanthemum, which starts to give way to 3D shapes. At this point a center of high-dimensional correlations between planes of experience starts bubbling up correlated subspaces for later use: planes, then 3D spaces, then hyper-planes, etc. And as these “high-dimensional Lego pieces” are made, they start becoming the elements of the scene (the walls, the objects, the space, the sense of presence, etc.).

Middle come-up (40-80 seconds): Crystal Worlds – In this phase of the experience there are a lot of “Buddhist no-self universes” of perfect resonance along many axes. Cave worlds, column worlds, pentagonal tiling of mirror chambers worlds, transparent blinds oceanic worlds, etc. There is a feeling that “these worlds exist independently of you” and that they are kinds of high-grade meditative states achievable by highly-attained monks and beings from other dimensions. They are sterile in some sense, though, which is that they lack evolution. They are attractor points of high-dimensional resonance. Insanely beautiful and ecstatic but also not perfect (for reasons that are hard to articulate).

Late come-up (80-100 seconds): Hyperbolic Gear World – At this point you start to see high-dimensional hyperbolic mechanisms. One intuitively feels that the state has too much energy to be contained in a Crystal World, which gives rise to stitching parallel Crystal Worlds into a unified hyperbolic world-sheet. Incredibly, this world-sheet is precise and seamless. The information contained in it is highly-specific. At this point number theory, hyperbolic geometry, and high-dimensional dynamics start to be very relevant. Irreducibly complex mathematical interlocking objects appear in very crisp and precise ways (it’s not just a fuzzy but intense impression of precision – it is a precise experience of precision clockwork machinery). 3D gear mechanisms with a prime-number of teeth that only repeat when they make as many cycles as the minimum common multiple of all the gears may show up, scenes with ‘plasma consciousness’ contained in hyperbolically-folded cavities with laminar color flow arise, spontaneous chaotic symmetry breaking devices arranged in the form of complex vibrating metallic flowers will materialize, etc. These devices also build on each other’s innovations. They can swap elements to become more interesting, more complex, more energetic, more hypnotizing, and more pleasurable than before.

Plateau (100-180 seconds): DMT Tykes – One starts to hallucinate things that are higher up in the visual hierarchy. “DMT Tykes” (another name for “DMT elves”) are humanoid forms that start to appear at this point. They are ever-evolving, and constructed of a high-dimensional hyperbolic world-sheet made of networks of interlocking Rabbit-Duck bistable percepts. In some sense the entities you see are not the DMT Tykes themselves. Instead, it feels like there are still higher-dimensional entities that interface with the space you’re at and it is those entities that control the rendered humanoid bistable percepts. The devices you saw in the immediately preceding stage (Hyperbolic Gear World) are revealed to be artifacts created by these higher-dimensional beings. As reported by others before, this space gives off the impression of being a gallery, a museum, a factory, or some kind of scientific testing facility, where entities are trying out new qualia configurations to study their properties: how they feel, what they can be used for, what it is like to experience them as a human being, etc. They are trying to compel you to take these things seriously, to see through how groundbreaking they would be for humans. Whenever one is too overwhelmed with the information presented (common misgivings are of the sort: “this is too much for a simple human” or “too beautiful, I don’t deserve this” or “what if people find out I know this?”) the experience becomes calming and things that you recognize as a human start being presented: jungles, hedonically-charged human scenes, locations, archetypes, stories about the origin of humanity, etc. And when one feels ready again to look at the complex machinery then there is this sense that the entities will continue to show you more and more of the irreducibly complex phenomenal objects native to that space.

Early comedown (180-240 seconds): High-Dimensional Breakdown – Entities may become a bit desperate to make sure they have sent along the most important information. The intensity starts subsiding and there is a lot of revisiting of earlier stages, gathering of essential insights, and decisions made about what to definitely try to bring back to one’s baseline state. Often one fears that one’s brain will never get back to normal during the earlier parts, but at this point one recognizes that there is a downward trend and that it’s all going to be ok after all. Paranoia, if present beforehand, starts to subside at this point. In terms of narrative, at this point one is usually coming to terms with what the experience will mean for your everyday life, whether you believe that the entities were real, and whether all of this was just a hallucination. The intuitive understanding that even if it is all just in your mind it still contained information of very high-value is clear at this stage (but may subside if you don’t properly encode it). Key undeniable facts of the experience at this point are: (1) there are heights of bliss and pain way outside of the range of human experience, (2) there are heights of mathematical complexity possible to experience directly that are beyond the scope of normal human cognition, and (3) there are types of qualia that matter both for intelligence and wellbeing that exist but humans are utterly clueless about. Disregarding the veracity of the entities or the literal interpretations of the experience, these three facts are straightforward to acknowledge at this stage of the trip.

Late comedown (240-360 seconds): Psychedelic Dampening – There is a clear sense that some of the information you were able to easily see and grock earlier in the experience is completely inaccessible now. You lose contact with what felt like higher forms of intelligence but you still see a lot of interesting patterns and complex geometry that you somehow realize is not as important as what happened just before. Even though it still feels like you are “very high”, it feels like one’s unique privileged access to information about consciousness is gone and that what you could discover now would not belong to the same level of “scientific breakthrough” as what you experienced before.

After-effects (360-600 seconds): Fast Sobering Up – Thinking about meta-narratives is very common at this stage, just like it is on traditional psychedelics. Things like “Where is the human world headed? What kind of consciousness will we experience as our default mode in 100 years from now? What will happen once scientists, engineers, and mathematicians start to do systematic research on the mathematics of the irreducibly-complex phenomenal objects at the peak of the experience? Etc.” Somewhere in along this stage the world finally becomes solidly uni-layered and then it just feels like a low dose of shrooms for a couple more minutes, at most.

Baseline (600 seconds onwards): Re-Grounding Stage – You start wondering what that was all about. The realization that you came back to normal again so quickly is likely to make you feel like you should have not been so afraid to try out the experience to begin with. At the same time, you also may feel a strong pull towards not experiencing that for a while (depends – some people feel braver at this point and redo the experience). In most circumstances one will feel a mood boost for several hours (up to days) for two reasons. First is the sense of significance and profundity in the form of gratitude and the feeling of being special that such an experience confers. And second, there seems to be an essentially physiological response to having gone through such an intense experience without getting harmed (if one wasn’t harmed, of course). Perhaps the annealing frame is adequate in this context. Namely, that the experience somehow smoothed out a lot of pinch points and imperfections latent in one’s psyche. The fear of “the worst that could happen to me” subsides and one experiences a sense of connection to other humans that is significantly above baseline.

Atman Retreat: Safe, Legal Psilocybin Experiences in Jamaica

Atman Retreat provides safe, legal psychedelic experiences outside of Montego Bay, Jamaica.

  • Upcoming retreat dates:
    • September 23-26 (7 spots left; as of September 2nd)
    • September 27-30 (5 spots left; as of September 2nd)
    • November 13-16
    • November 17-20
       
  • Atman recently introduced tiered pricing and a low-income ticket program.

About Atman Retreat (source)

Psychedelics are known to produce profound, meaningful, transformative experiences when used in a safe and intentional manner.1 However, many people don’t have access to psychedelics, or to a safe setting within which to use them. Others simply don’t want to break the law. Until we adopt more compassionate, evidence-based drug policy, there are few ways for people to experience these extraordinary states of consciousness safely and legally. Atman Retreat exists to fill this gap.

Our core mission is to help people explore the full potential of the psychedelic experience, in all its healing, transformative, and transcendent qualities. Retreats are held in Jamaica, where psilocybin mushrooms are legal. Participants stay at a spacious villa, with comfortable rooms and a scenic private beachfront. Our team of experienced facilitators is passionate about creating space for inner transformation, insight, and breakthroughs.

Whether you’re completely new to psychedelics, or a seasoned psychonaut interested in a different kind of journey, Atman Retreat is a complete 4-day experience that allows you to explore psychedelics safely, legally, and in a setting designed to maximize their benefits.

When you feel ready, you can apply here.



Why am I sharing this announcement? I think that Atman Retreat is especially suited to Qualia Computing readers for the following three reasons:

  1. I know some of the people who started it and I can confirm that they are good, rational, and tactful people trying to make the world a better place.
  2. The retreat is open-ended in nature. Sadly, most legal psychedelic retreats come with heavy “memetic baggage” in the form of unquestioned beliefs about spirituality or strong ideological commitments. At the very least, the focus of most legal psychedelic retreats is explicitly therapeutic. Atman Retreat is a good place to simply explore your own mind and study the nature of consciousness without having to accept any spiritual, therapeutic, or ideological framework. For example, their website has a research section which lists and summarizes recent studies on the effects of psilocybin, which shows a willingness by the staff to engage with a scientific approach to psychedelics.
  3. The participants in previous cohorts of Atman Retreat have been very aligned with both Effective Altruism and the scientific study of consciousness. In other words, the attendees are typically smart, curious, ethical, and epistemologically sound.

To this, I will add that one of the visions of the Qualia Research Institute is to create an empirical consciousness research center in which psychedelics are taken by the brightest scientists, philosophers, and engineers to explore alien state-spaces of consciousness directly.

Indeed, consciousness research is currently at a pre-Galilean state, where brain scientists refuse to “look through the telescope” so to speak (or at least if they do, they are not talking about it publicly). Scientific culture is such that discussing the EEG measurements of members of the general public under the influence of psychedelics is acceptable but as soon as one talks about one’s own direct experience with such compounds one’s scientific credibility becomes suspect.

We can change this, and one of the first steps is to establish a legal framework for consciousness researchers to be able to engage in fruitful self-experimentation. Real scientific progress on consciousness will only take place with a twin track that combines both analysis of third-person data and the use of an empirical research methodology of direct experience by the researchers themselves. By pointing to the Atman Retreat I am hoping to elevate it to the status of a sort of Schelling point for rational psychonauts to converge on for the time being.

Perhaps this is a crucial first step in establishing a legally-viable Super-Shulgin Academy* for a post-Galilean science of consciousness.

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Jamaica is waiting for you!



*From the QRI Glossary

Super-Shulgin Academy (coined by David Pearce; ref: 12345678): This is a hypothetical future intellectual society that investigates consciousness empirically. Rather than merely theorizing about it or having people from the general population describe their odd experiences, the Super-Shulgin Academy directly studies the state-space of consciousness by putting the brightest minds on the task. The Super-Shulgin Academy (1) trains high-quality consciousness researchers and psychonauts, (2) investigates the computational trade-offs between different states of consciousness, (3) finds new socially-useful applications for exotic states of consciousness, (4) practices the art and craft of creating ultra-blissful experiences, and (5) develops and maintains a full-stack memeplex that incorporates the latest insights about the state-space of consciousness into the most up-to-date Theory of Everything.

Featured image: source.

Kaleidoscopic Integration: Annealing, Symmetry, and the Information Theory of Experience

Symmetric_pattern_drifting

HP: What exactly is “symmetrical texture repetition”?

JE: Symmetrical texture repetition is just one of many complex visual distortions or alterations which consistently occur throughout psychedelic experiences on substances such as LSD, Psilocin, Ayahuasca, Mescaline, 2C-B, 2C-E and many others.

It can be described as the organization of rough textures within the external environment becoming mirrored repeatedly over its own surface in an extremely intricate and symmetrical fashion that is consistent across itself. This remains at an unchanging level of extremely high detail and visual clarity within both a person’s direct line of visual focus and peripheral vision.

 

As these repeating textures are generated they begin to give rise to a huge array of abstract forms, imagery, geometry and patterns that are perceived to be embedded within and across the symmetry.

 

Interview with Chelsea Morgan, a prolific and talented psychedelic replication artist

Towel (1)

Towel texture enhancement by Chelsea Morgan. Source.

Ice_by_Chelsea_Morgan

Ice symmetrical texture repetition by Chelsea Morgan. Source.

How it feels like to symmetry-unify from the inside, a case study:

Onion Article Headline 2016: Synesthetic Couch-Texture Not Quite Ready to Merge with Lamp Turned Space-Filling Line System, Says It Needs to Make Itself More Spiky First

 

Inside Alice’s acid-filled brain today, we are now about to experience for the 6th time or so how various blobs of textures are trying to merge into a coherent super structure. According to local sources, Alice is currently feeling a sense of awe and anticipation as the two big texture clusters in her field of vision are beginning to interact with each other. She is excited to notice that one of them is “calling” the other into it, and giving it ideas on how to “plug in geometrically” with it.

 

Alice, who reportedly took 160 micrograms of LSD roughly 3 hours ago, narrates how it felt like to make a super-symmetrical system in her visual-kinesthetic field for the 5th time:

 

“I don’t know if this was the result of alien intelligences messing up with my brain, perhaps a mystical vision about how my ancestors’ experiences connect to mine, or if it was just a strange quantum-entanglement phenomenon in consciousness currently undocumented in the scientific literature, but duude! That one time the couch texture blob made itself more spiky in order to merge with the the space-filling lamp… that was awesome. I look forward to it happening again, but now also including the carpet, walls, and my hands. Leave no texture behind – the resonant symmetry super-structure can make room for everyone.” – Said Alice, in closing.

Psychedelic Symmetry: A Window Into the Information-Theoretic Properties of Experience?

My friend Tim who had not done LSD for many years, responded to this sudden 5 hit dose by going into a state of complete dissociation. He lay down on the forest floor with glassy eyes, muttering “It is TOO beautiful! It is TOO beautiful!” and he did not respond to me, even when I stared him straight in the face. He reported afterwards that he found himself in a giant Gothic cathedral with the most extravagantly elaborate and brightly painted ornamental decorations all around him. This too can be seen as an extreme form of the regularization discussed above. Under the influence of this powerful dose, Tim’s visual brain could no longer keep up with the massive irregularity of the forest around him, and therefore presented the forest in simplified or abbreviated form, as the interior of a Gothic cathedral. It captures the large geometry of a ground plane that supports an array of vertical columns, each of which fans out high overhead to link up into an over-arching canopy of branches. The only difference is that in the Gothic cathedral the trees are in a regular geometrical array, and each one is a masterpiece of compound symmetry, composed of smaller pillars of different diameters in perfectly symmetrical arrangements, and studded with periodic patterns of ribs, ridges, or knobby protuberances as a kind of celebration of symmetry and periodicity for their own sake. There is a kind of geometrical logic expressed in the ornamental design. If part of the cathedral were lost or destroyed, the pattern could be easily restored by following the same logic as the rest of the design. In information-theoretic terms, the Gothic cathedral has lots of redundancy, its pattern could be expressed in a very much simpler compressed geometrical code. In Tim’s drug-addled brain his visual system could only muster a simple code to represent the world around him, and that is why Tim saw the forest as a Gothic cathedral. Under normal conditions, the additional information of irregularity, or how each tree and branch breaks from the strict regularity of the cathedral model of it, creates the irregular world of experience that we normally see around us. This suggests that the beautiful shapes of ornamental art are not the product of the highest human faculty, as is commonly supposed, but rather, ornamental art offers a window onto the workings of a simpler visual system, whose image of the world is distorted by artifacts of the representational scheme used in the brain. The Gothic cathedral gives a hint as to how the world might appear to a simpler creature, a lizard, or a snake, to whom the world appears more regular than it does to us, because its full irregularity is too expensive to encode exhaustively in all its chaotic details. Of course the flip-side of this rumination is that the world that we humans experience, even in the stone-cold sober state, is itself immeasurably simpler, more regular and geometric, that the real world itself, of which our experience is an imperfect replica. In the words of William Blake, “If the doors of perception were cleansed, everything would appear to man as it is, infinite.”

– “The Grand Illusion” by Cognitive Scientist Steven Lehar

960


What is the information content of a gothic cathedral? What percentage of it needs to burn down to make it impossible to reconstruct from the ruins alone?

Why Does Any of This Matter? The Deceptively Profound Implications of Psychedelic Symmetry According to Cognitive Scientist Steven Lehar

But there was one aspect of the LSD experience that had me truly baffled, and that was the fantastic symmetries and periodicities that were so characteristic of the experience. What kind of neural network model could possibly account for that? It was an issue that I grappled with for many months that stretched into years. In relation to Grossberg’s neural network, it seemed that the issue concerned the question of what happens at corners and vertices where contours meet or cross. A model based on collinearity alone would be stumped at image vertices. And yet a straightforward extension of Grossberg’s neural network theory to address image vertices leads to a combinatorial explosion. The obvious extension, initially proposed by Grossberg himself, was to posit specialized “cooperative cells” with receptive fields configured to detect and enhance other configurations of edges besides ones that are collinear. But the problem is that you would need so many different specialized cells to recognize and complete every possible type of vertex, such as T and V and X and Y vertices, where two or more edges meet at a point, and each of these vertex types would have to be replicated at every orientation, and at every location across the whole visual field! It just seemed like a brute-force solution that was totally implausible.

Then one day after agonizing for months on this issue, my LSD observations of periodic and symmetrical patterns suddenly triggered a novel inspiration. Maybe the nervous system does not require specialized hard-wired receptive fields to accomodate every type of vertex, replicated at every orientation at every spatial location. Maybe the nervous system uses something much more dynamic and adaptive and flexible. Maybe it uses circular standing waves to represent different vertex types, where the standing wave can bend and warp to match the visual input, and standing waves would explain all that symmetry and periodicity so clearly evident in the LSD experience as little rotational standing waves that emerge spontaneously at image vertices, and adapt to the configuration of those vertices. Thanks to illegal psychotropic substances, I had stumbled on a staggeringly significant new theory of the brain, a theory which, if proven right, would turn the world of neuroscience on its head! My heart raced and pounded at the implications of what I had discovered. And this theory became the prime focus of my PhD thesis (Lehar 1994), in which I did computer simulations of my harmonic resonance model that replicated certain visual illusions in a way that no other model could. I had accomplished the impossible. I had found an actual practical use and purpose for what was becoming my favorite pass-time, psychedelic drugs! It was a moment of glory for an intrepid psychonaut, a turning point in my life. Figure 2.6 shows a page from my notebook dated October 6 1992, the first mention of my new theory of harmonic resonance in the brain.

– “The Grand Illusion” by Cognitive Scientist Steven Lehar

lehar_2_6


Featured image credit: Simon Haiduk

Carhart-Harris & Friston 2019 – REBUS and the Anarchic Brain

Reposted from Enthea with permission from the writer: 


Drs. Robin Carhart-Harris and Karl Friston recently published a beautiful paper – REBUS and the Anarchic Brain (a).

It’s great for two reasons:

  1. It presents a plausible unified theory of how psychedelics work.
  2. It’s a wonderful jumping-off point into the literature. Every paragraph is full of pointers to research that’s come out in the last 5 years, and boy are there a lot of rabbit holes to go down – it’s filled out my reading list for the next several months.

Carhart-Harris is the director of Imperial College London’s newly minted Centre for Psychedelic Research; Friston is a famous neuroscientist.

REBUS is a (somewhat dubious) acronym for RElaxed Beliefs Under pSychedelics. The basic idea: psychedelics reduce the weight of held beliefs and increase the weight of incoming sensory input, allowing the beliefs to be more readily changed by the new sensory information.

REBUS pulls together Carhart-Harris’ Entropic Brain theory and Friston’s Free Energy Principle, both of which relate to the hierarchical predictive coding model of cognition. There’s a lot of jargon & nuance here, but the essential idea of hierarchical predictive coding is pretty straightforward:

  • The brain generates mental models that predict upcoming sensory inputs. (The predictions are called “priors,” as in “prior beliefs.”)
  • These predictive models are layered on top of each other in a hierarchy – the higher levels send predictions down the hierarchy; the lower levels report sense data upwards.
  • In cases where the model’s top-down predictions do not match the bottom-up sensory input, the model either (a) updates its priors based on the new sense data, or (b) ignores the sense data and maintains its priors.

(Scott Alexander’s review of Surfing Uncertainty has a lot more on predictive coding.)

Carhart-Harris & Friston theorize that the main thing psychedelics are doing is relaxing the weight of the brain’s top-down prediction-making (“REBUS”) and increasing the weight of the bottom-up sense information (“the Anarchic Brain”). This allows bottom-up information to have more influence on our conscious experience, and also on the configuration of the hierarchy overall.

Carhart-Harris & Friston analogize this process to annealing – heating up a metal dissolves its crystalline structure, then a new structure recrystallizes as the metal cools:

The hypothesized flattening of the brain’s (variational free) energy landscape under psychedelics can be seen as analogous to the phenomenon of simulated annealing in computer science – which itself is analogous to annealing in metallurgy, whereby a system is heated (i.e., instantiated by increased neural excitability), such that it attains a state of heightened plasticity, in which the discovery of new energy minima (relatively stable places/trajectories for the system to visit/reside in for a period of time) is accelerated (Wang and Smith, 1998).

Subsequently, as the drug is metabolized and the system cools, its dynamics begin to stabilize – and attractor basins begin to steepen again (Carhart-Harris et al., 2017). This process may result in the emergence of a new energy landscape with revised properties.

Psychedelics “heat up” the brain, increasing plasticity and weakening the influence of prior beliefs. As the psychedelic stops being active, the brain “cools” – the hierarchy re-forms, though perhaps in a different configuration than the pre-psychedelic configuration.

This explains how psychedelic trips can cause changes that last long after the substance has exited the body – in those cases, the psychedelic facilitated a change in the organization of the brain’s cognitive hierarchy.

Psychedelic therapy is showing promise for mental disorders associated with too-rigid thought patterns – depression, anxiety, addictions, maybe OCD, maybe eating disorders. In predictive-coding lingo, “disorders that may rest on particularly rigid high-level priors that dominate cognition.”

In these disorders, new information can’t revise the existing story of how things are, because strong priors suppress the new info before it can update anything.

The REBUS model straightforwardly explains how psychedelics help with disorder like this – by relaxing the strong top-down priors and boosting the bottom-up inputs, bottom-up inputs have more ability to effect the system. Here’s an illustration from the paper:

rebus-schema

The top sketch is a brain where strong top-down priors dominate. New sensory inputs are suppressed and can’t update the hierarchy. The bottom sketch is the same brain while on a psychedelic – the top-down priors have been relaxed and bottom-up sensory information flows more freely through the system, causing a bigger impact.

Okay, nice theory, but can we observe this in the brain? Is there any evidence for it?

Carhart-Harris & Friston place the default mode network at top of the brain’s predictive hierarchy. The default mode network is the network of brain regions that’s most active when the brain isn’t engaged with any specific task. It also appears to be the seat of one’s sense of self. The default mode network is intensely relaxed by strong psychedelic experiences – this is subjectively felt as ego dissolution, and allows for the propagation of bottom-up sense data (which are also boosted by psychedelics).

Carhart-Harris & Friston identify two mechanisms by which psychedelics may relax the default mode network – activation of 5-HT2AR serotonin receptors (there are lots of these receptors in the default mode network), and disruption of α and βwave patterns, which seem to propagate top-down expectations through the brain (and are correlated with default mode network activity).

In addition to the brain-scan-style evidence they cite throughout the paper, Carhart-Harris & Friston dedicate a long section to behavioral evidence (“Behavioral Evidence of Relaxed Priors under Psychedelics”). Briefly, there are several studies showing that surprise & consistency-making responses to sensory stimuli are reduced while on psychedelics, which is what we’d expect if the influence of top-down priors was lessened.

To sum up, REBUS and the Anarchic Brain places psychedelics in a predictive coding framework to give a unified theory of what psychedelics do – they decrease the influence of top-down prediction-making and increase the influence of bottom-up sense data. The theory has the nice quality of tying many disparate psychedelic phenomena together with an underlying explanation of what’s going on. Plus, it gives a brain-based explanation for why psychedelic therapy is helpful for disorders like depression, anxiety, and addiction.



See also: Mike Johnson’s pieces A Future for Neuroscience and The Neuroscience of Meditation which summarize a lot of the research by the Qualia Research Institute (QRI) on this topic. In particular, much like this paper by Carhart-Harris and Friston, at QRI we’ve been working on integrating the neuroscientific paradigms of Entropic Brain, Connectome-Specific Harmonic Waves, Predictive Coding, and our own contribution of Neural Annealing into a unified theory of psychedelic action for a number of years.

Our first mention of Neural Annealing in relation to psychedelics was in Algorithmic Reduction of Psychedelic States in 2016, and we are pleased to see that the concept is becoming a live idea in academic neuroscience in 2019.*

From our point of view, an extremely promising area of research that mainstream neuroscience has yet to explore is the Symmetry Theory of Valence. In particular, we claim that the very reason why Neural Annealing improves not only global control, belief, and behavioral consistency, but also mood and sense of wellbeing is because it smooths and symmetrifies your neural patterns of activation. Will this turn out to become part of mainstream neuroscience in the future? Well, since QRI was calling Neural Annealing years in advance, perhaps in retrospect you’ll also see that we were on the money when it came to the mathematics of valence. Only time (and funding) will tell.


*It should be noted that unbeknownst to us Steven Lehar might be the first person to discuss neural annealing in the context of psychedelic states of consciousness. In his 2010 book “The Grand Illusion” he talks about annealing on LSD and ketamine. Here are some key articles about it: Free-Wheeling Hallucinations, The Resonance and Vibration of [Phenomenal] Objects, The Phenomenal Character of LSD + MDMA, and From Point-of-View Fragmentation to Global Visual Coherence: Harmony, Symmetry, and Resonance on LSD.


Featured image credit: Michael Aaron Coleman

Using Ibogaine to Create Friendlier Opioids

by Quintin Frerichs

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?

Capsaicin_chemical_structure

Capsaicin (source)

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.

Agonist_2

Full vs. partial agonists (source)

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 DemeRX for 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/

Featured image source: What Is Iboga?

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

5-MeO-DMT Trip Report by Anonymous Reader

Dose: Two 7mg hits separated by about 15 minutes.

Context: The writer of this trip report suffers from anhedonia. One of the main motivations for trying 5-MeO-DMT was to see if it could help with such anhedonia.


Oh my god. The emotion. Pure intense pain. The situation was so moving. I knew I was in a state where I couldn’t not empathize with the pain. Coming out of it I felt like I was being let in on the lesson. My social barriers weren’t formed yet and I felt like we’re all melded in one family of empathized minds. There was no hiding or not acknowledging the immensity of pain. The lesson was “This is what is possible. This is what is happening to someone. This is very serious.” But it wasn’t just that recognition. There was a social experience, almost like an induction.

The come up was physically pleasant but very fast and then became very negative and high intensity. I think if I had my normal connection to my body, I’d be gripping the chair arm in pain and grunting, possibly weeping, but one thing I noticed about the experience was that there was a lack of strength to any aversions or fears or rejections, let alone expressions thereof. In ordinary sober life, something that negative would lead me to react with aversion.

Unlike the (less) painful experience of eating habanero peppers, I regarded the experience very sincere and true. Ordinarily I’m very wary of fanaticism and sentimentalism and social pressures and tragedies of the commons etc… to the point of social and emotional non-participation in society. I realize this is pathological so I try to get past my social cynicism and inhibition. This experience definitely put me right into a state of embracing a social consensus and I had very little ability to squirm or object to whatever indoctrination I could have seen it as. From the outside a social experience looks like indoctrination, but from the inside it is genuine and true. Beneath fanaticism is genuine empathy and significance, and I realized this when coming out and crying and sighing and making other social expressions at the message I had just received, having the sense of empathy transcend all social transactions of which I’m cynical.

There was a sense of magnetism and attraction both to this blazing core of serious suffering in the peak of the experience and the beautiful blue drawing undercurrents of the high valence, lovely come down, which lasted a good 15 minutes. The content of the experience was very unified and simple. “General” is the word that I think best describes the content. It includes the ontologies normally attributed to specific concepts. It includes these but isn’t reduced to them. Very general state of thinking. “Feeling” might be a good word for the general state underlying particular “thoughts.” And perhaps it was this general freedom which added to the impression that it broke through my social cynicisms.

The part that stood out for me was the emotion. I’ve never experienced emotion that strong before and it was useful to be reminded of what emotions feel like. There are levels of intensity and depth of emotion that mustn’t be forgotten. I dream of the life where I can tap into an infinite river of significance-rich, intense emotion. I felt in the trip an endlessly self-powering current of pure emotional energy blasting away (negative in the peak) and then undertows of deep oceanic bliss emotions of wellbeing and peace in the come down. Sometimes when I’m coming off a long, multi-day fast with a meal and my hormones and neurotransmitters are changing I feel emotional. Sometimes when I’ve gone a long time without hearing music and I play some great Bach cantata really loudly, I feel a bit of that moving emotional significance again. Interestingly I didn’t really separate the intensity from the significance during the trip. They felt one and the same. All meaning and sense of echoes and ramifications and contexts seemed to simply be unified in that general unified blazing entity of pure undifferentiated intensity. Yet, it didn’t feel insignificant, even though it lacked more specific content.

I think this might help with suffering because it does two things. One is that in my experience one has little choice to resist. Embracing an experience rather than struggling with it prevents unnecessary suffering. It also gives a state of pure, undifferentiated feeling which sort of envelops pain. This is good because it shows you the “unreality” of your thoughts. When you’re in an emotional state there’s a feeling behind the thoughts and different thoughts come in to support that feeling, but contending with them individually only multiplies them. It’s easier to just address the entire feeling at once. It’s hard to say how bad that experience was when all my aversion and struggling and resisting and fighting were disabled… I couldn’t protest the experience—does that cause me to infer in my memories that it must not have been worthy of resistance and therefore dispose me to take more when really it would be suffering that I would otherwise resist and avoid in the future? All I can say was that coming out of it I was very grateful, and not grateful that it was over but grateful that I had seen such truth for the sake of truth, and then the comedown incidentally turned nice and quite pleasant.

The come-off felt very slow and beautiful. Imagine taffy hanging over a rotating disk, like a lazy Susan. It felt like I was this taffy and passing beneath me was this undertow and after a delay it would pull me under in a pulse of pleasure. Or say there’s a car and a string tied to it and on the other end your tooth, and as soon as you’d have a thought the car would start running with that string and as the slack gets pulled with the car you might get distracted but then you’d eventually have your tooth pulled and you’d have your attention brought back to a string you might not have realized was there all the time. That’s what the long delayed slow crescendo pleasantnesses of the comedown of it would do for all kinds of thoughts and images and experiential events. To find out after a long delay that all this time a thought you had several seconds ago is still going on is quite reassuring—well, in this case it was. And these tooth pulls were quite pleasurable for some reason. And along with it came the bodily sensation of being magnetically drawn toward this thing.


Since going on an SSRI in 2015 (which I discontinued after 10 months in 2015), I’ve suffered chronic anhedonia (note that this paragraph was written over a week after the experience, where most of the report was written the day after, such as the exclamatory first sentences “Oh my god. The emotion,” which I was able to express because my body was still giving me a fresh enough memory of the experience from the night before. I’ve since lost emotional connection/recollection of the experience). I find I do suffer, but I lack any sense of it mattering. In particular, there’s a lack of a coordination between my frontal lobes and my limbic system (and SSRI’s can reduce the connectivity between the limbic system and the cortex… kind of like a mild chemical frontal lobotomy…), so any complex understanding of things like life situations or future plans or anything that takes the “high road” in the fear/emotional response through the cortex, get’s processed by the cortex but not communicated to the limbic system. So I can suffer, and I can verbally understand I’m suffering, but I can’t see why that matters or why I should do anything about it. I can’t emotionally reason. I can’t envision things that excite me. I can’t come up with reasons to alleviate ongoing anxiety like I used to. Before the SSRI, I’d have a pessimistic or anxious or sad thought and then I’d intervene with reasoning and “take perspective” and realize why things are ok after all or why something IS worth doing. None of that thinking reasoning gets through now. It seems only very immediate physical things with little dependence on the cortex get a somewhat appropriate level of emotional arousal out of me, like a car accident or crudely apprehended social threats/stress. I also have lots of indecision and waste time in dull thought loops. My thoughts lack emotional potency and they fail to support decision making. The experience of 5-MeO-DMT reminded me that suffering does matter, that things do matter, there is emotional significance. Because of the state depends of memory, I can’t really access that much, though in the days following the experience my body did find a certain posture that would trigger a strong recollection of the experience. It feels like I’m in flatland and this experience is in the third dimension, the dimension of emotional significance, and my frameworks presently don’t allow me much access to these memories, but I am grateful for the experience and the long come down which allowed me to take into my cortex the verbal/generic memories of the fact emotional stuff is real, and is out there. It restored hope and reminded me of the goal of getting out of this anhedonia. It’s better to live in hope and some optimism, even if success is futile. Just look at very old or obese people who still take care of their appearance with grooming.


See also: Trip reports by anonymous Qualia Computing readers for LSD2C-B, and 4-AcO-DMT.

Ego and Symmetry on 5-MeO-DMT

Transcript from: Using 5-MeO-DMT To Become Enlightened – Interview With Martin Ball (~43:00 – 47:00)


Martin Ball: Here is what I learned very quickly in working both with 5-MeO-DMT and other medicines during the same time period. First, I noticed this in myself, and then I started looking to see if this was true for other people, and very quickly found that this was true. There is a fundamental distinction: when people go into fully energetically open non-dual states of awareness -and I do qualify it with ‘fully energetically open’ because that is different than, say, a meditative non-dual experience, which I do not qualify as energetically fully open- when someone is energetically fully open and goes into a non-dual state of awareness, what happens is that they always open up with a perfectly mirrored bilateral symmetry, with the left and right sides of the body always mirroring each other. And nothing ever crosses the center line of the body. People move spontaneously or their bodies open up, and their hands may come together, but they come together right here, in the middle along the center line, and then they separate, and then come back together. Then you can see a transition when suddenly someone comes back into the ego. So, they are fully immersed in the experience and their bodies are opened… and then as soon as the ego comes in, there is some kind of break when suddenly the left side of the body is doing something different than the right side of the body.

For people who don’t get all the way to being fully energetically open, you give them a very powerful psychedelic -which again is changing the energetic experience of the body- and you can watch them fight with it, and you will see that there is always some kind of asymmetry taking place in their body language when they are fighting with it. Or if they are still residing in their ego. So I learned very quickly that non-dual states of awareness coincide with balanced bilateral symmetry and the ego almost always functions through some form of energetic asymmetry. Which is perfectly natural! I mean, there is noting wrong with it, I am not trying to criticize it. But for example (I use this example all the time): My glass of water is to my right. Now if I -a subject- become thirsty and I want my water, operating with bilateral symmetry isn’t going to get me my water. My water is over here to the right. So I break into object-subject duality so we can have an interaction between these two different parts of the self. So working with psychedelics for the intention of achieving… not only achieving, but also working out the distortions of the ego, means paying attention to how either symmetries or asymmetries show up within the body.

So this is the challenge that I give people: Take some 5-MeO-DMT, and see how long you can stay perfectly symmetrical within your body. Now, some people can ride it all the way through. And they can do that fairly easily. Many people… I would say the vast majority, can’t. And even those who do, who open up initially and are in this nice bilateral symmetry, you will see, after 10 or 15 minutes, or for some people after 30 seconds, as soon as the ego starts to reintegrate, they start breaking into asymmetries. Now, what can happen is… so the ego itself, and this is also coming out of my own experience, this is not based on anybody else’s model, this is just my own definition of the ego… the ego itself is not a singular thing. It is a collection of patterns of energy. So as we are coming into ourselves, as young beings, what we are doing is learning different -what we perceive as acceptable- ways of engaging our energy.