The Fact That We Can Smell Functional Groups is Just Such a Thing

[Excerpt from The Secret of Scent (2006) by Luca Turin, pgs 108-111]

Some Strange Clues

It has been said,* correctly in my opinion, that theories define facts as much as the other way around. Nowhere is this more true than in structure-odour relations, where all knowledge is anecdotal. Anecdotal evidence has a sort of slippery, jelly-like quality to it, and theories are needed to congeal the stuff together into single, solid facts. ‘Anecdotal’ is often used as a pejorative term in scientific circles, meaning unreliable. In practice it often means isolated, and therefore hard to assess. Think of a new field of science as a large jigsaw puzzle. Pieces are discovered one by one, and at first they are unlikely to fit together to make a picture. Things can look distinctly unpromising, sometimes for decades. But if you can bear the pain of feeling stupid and the humiliation of being wrong, anecdotal evidence is the call of the wild, the surest sign of the undiscovered. Columbus set sail on the basis of anecdotal evidence. The Mayan hieroglyphs were deciphered using anecdotal evidence. Life-saving remedies based on plants, such as aspirin and digitalis, were found by scientists who paid attention to anecdotal evidence.

Scientific problems typically go through three phases. In the first phase, a few bold explorers discover a new land and map out its basic features. In the second phase, boatloads of immigrant scientists arrive and colonize the land. In the third phase, statues are erected on town squares, sometimes to the original discoverers, more often to the able administrators who build the roads and railways. Smell, as it happens, did not follow this pattern. Scientific colonies never thrived on this particular island. Every few years, a new set of scientists claims to have cleared the jungle, but their cities are eventually overgrown and get lost in the weeds.

In smell, the difficulty is compounded by two additional factors, one obvious, the other more subtle. The first is the supposed untrustworthiness of the smell sensation I’ve mentioned earlier which makes strong men and women doubt their own noses. The second is that when facts, especially anecdotal ones, remain unexplained for long enough, a kind of question fatigue sets in, and they become accepted without being understood. The situation brings to mind a quintessentially British cartoon I saw once where a dinosaur strides past a terraced house, and a couple see it from their living room. Wife: “What was that?” Husband: “Oh, just one of those Things.” The fact that we can smell functional groups is just such a Thing.

Functional groups, as we have seen, are the specific structures of one or more atoms that are responsible for the chemical behaviour of a substance. Examples are thiols (-SH), nitriles (-CN), and aldehydes (-C(=O)H). The little hyphen indicates that these groups are, of course, attached to something and that the Something varies hugely. But the remarkable thing is that the Something matters little to the smell of the molecules. What gives the game away, especially to the casual observer, is the fact that types of smell are named after chemical groups: sulphuraceous, nitrilic, aldehydic, corresponding respectively to -SH, -CN, -(H)C=O. This is particularly clear in the case of -SH. All molecules which contain an -SH group smell (a) strong and (b) reminiscent of rotten eggs.

A word about the description ‘rotten eggs,’ since only a tiny minority of readers will be old enough to remember them. Eggs nowadays come with time stamps and serial numbers, so they seldom get a chance to rot. The rotten eggs smell is today more likely to be experienced in an oriental market (the durian fruit), by opening the gas tap on the stove (a small amount of an -SH compound is added to make sure we notice it), or best of all by going to an Indian store and asking for kala namak or ‘black salt’. Black salt, as its name does not indicate, is actually pink and is a type of rock salt that must come from Hell, as it contains ample amounts of Hell’s Kitchen smell, namely the HSH molecule. HSH is -SH repeated and smells bad twice over. Put some kala namak on your tongue and you will see what I mean. The first thing you will notice is that it reminds you mostly of a very intense hard-boiled egg smell. Clearly, eggs, even when fresh, are itching to fall apart. If you’ve done any chemistry at school, you will also recall the classroom when the teacher was making one of those stinks for which chemistry is famous. Beware though, the culinary satanism of kala namak is beguiling: a tiny amount in blackcurrant ice cream, strawberry daiquiris, coffee, and chocolate does wonders, as long as you don’t let anyone know you did it.

Do all -SH compounds smell identical then, i.e. of rotten eggs? Not a bit, actually: they smell of all manner of things, from grapefruit to garlic via blackcurrants,  but they all have this sulphuraceous (i.e. from Hell) character. The grapefruit compound is particularly instructive. It is called pinanethiol. Thiol means -SH, so pinanethiol means pinane-SH.

Remove the -SH and the rest of the molecule (pinane) smells like pine needles, as it should, since pinane is a major component of turpentine oil, itself extracted from pine. Add the -SH back and, having smelled the pinane by itself and familiarized yourself with kala namak, you can clearly smell the parts of the molecule. That is to say you smell both the pine needles and the sulphur. Smell another very strong -SH compound like H₃C-SH, or methanethiol, for a few seconds till the nose (mercifully) tires of the hideous -SH smell, then go back to pinane-SH. Surprise! The sulphur note is now almost gone and the molecule no longer smells of pinane-SH, but instead smells of pinane tout court. This means that this molecule smells like the sum of its parts. In other words, -SH is a primary, though the other smells are not. But how does that work? How do we know what parts it’s made of? This, as we shall see, is the greatest mystery of smell. Looking for an answer will take us amazingly far afield.


* Paul Feyerabend, among others, convincingly argued this view in Against Method, required reading for those who believe the scientific method is something which can be written down and followed like a recipe.



Comments:

On a recent conversation I had with Luca, I shared with him the fact that there are anti-tolerance drugs that can lessen (and even reverse) the physiological tolerance to drugs such as painkillers. He was seriously surprised by this fact. Despite spending a whole career studying biological regulatory systems, he had never in his life heard of anti-tolerance drugs in academia. Upon hearing this, he shared that in his experience, most of the innovation in science comes from people who work hands-on in the field, as this exposes them to a much broader evidential base than you would encounter when doing research in a strictly theoretical way.

Thus, he has learned far more about consciousness from psychonauts than he ever has from academic psychopharmacologists, and has learned more about electronics from radio amateurs than professional electrical engineers. In other words, the people who actually tinker with the inner mechanisms of the systems they’re interested in are the people to ask for “weird and novel phenomena”, rather than (only) those who study the field academically angling for a university post or a narrow job in the industry. Same, of course, with the science of smell: actually tinkering with aromachemicals can give rise to discoveries one may never stumble upon by merely studying scent receptors in a lab. Needless to say, the best outcomes will come from seamlessly blending both worlds; but for that to happen we will have to embrace phenomenological reports as acceptable leads for research in science.

See Luca Turin’s recent series on the science of smell on youtube: The Secret of Scent (including a video on the objections to the vibrational theory of olfaction).

5-MeO-DMT Awakenings: From Naïve Realism to Symmetrical Enlightenment

In the following video Leo Gura from actualized.org talks about his 30-day 5-MeO-DMT streak experiment. In this post I’ll highlight some of the notable things he said and comment along the way using a QRI-lens to interpret his experiences (if you would rather make up your mind about what he says without my commentary just go and watch the video on your own before reading what I have to say about it).

TL;DR: Many of the core QRI paradigms such as Neural Annealing, the Symmetry Theory of Valence, the Tyranny of the Intentional Object, and Hyperbolic Geometry on Psychedelics have a surprising degree of explanatory power when it comes to making sense of the peculiar process that ensues when someone takes a lot of 5-MeO-DMT. The deep connections between symmetry, valence, smooth geometry, and information content are made clear in this context due to the extreme and purified nature of the states induced by the drug.


Introduction

Recently Adeptus Psychonautica (who has interviewed me in the past about the hyperbolic geometry of DMT experiences) put out a video titled “When you have taken too much – Actualized.org“. This video caught my attention because Leo Gura did something that is rather taboo in spiritual communities, and for good reasons. Namely, he tried to convince the viewers that he had achieved a level of awakening that nobody (or perhaps only a few people) on the entire planet had ever reached. He then said he was going to isolate for a month to integrate these profound awakenings and come back with a description of what they are all about.

Thankfully I didn’t have to wait a month to satisfy my curiosity and see what happened after his period of isolation because by the time I found about it he had already posted his post-retreat video. Well, it turns out that he used those 30 days of isolation to conduct a very hard-core psychedelic experiment. Namely, he took high doses of 5-MeO-DMT daily for the entire month. I’ve never heard of anyone doing this before.

Learning about what he experienced during that month is of special interest to me for many reasons. In particular, thanks to previous research about extreme bliss and suffering, we had determined that 5-MeO-DMT is currently the psychedelic drug that has the most powerful and intense effects on valence. Recall Logarithmic Scales of Pleasure and Pain (video): many lines of evidence point to the fact that extreme states of consciousness are surprisingly powerful in ways that are completely counterintuitive. So when Leo says that there are “many levels of awakening” and goes on to discuss how each level is unrecognizably more intense and deeper than the previous one, I am very much inclined to believe he is trying to convey a true property of his experiences. Note that Leo did not only indulge in psychedelics; we are talking about 5-MeO-DMT in particular, which is the thermonuclear bomb version of a psychoactive drug (as with Plutonium, this stuff is best handled with caution). More so, thankfully Leo is very eloquent, which is rare among people who have had many extreme experiences. So I was very eager to hear what he had to say.

While I can very easily believe his trip reports when it comes to their profundity, intensity, and extraordinary degree of consciousness, I do not particularly find his interpretations of these experiences convincing. As I go about describing his video, I will point out ways in which you can take as veridical his phenomenological descriptions without at the same time having to agree with his interpretations of them. More so, if you end up exploring these varieties of altered states yourself, by reading this you will now at least have two different and competing frameworks to explain your experiences. This, I think, is an improvement. Right now the psychedelic and scientific community has very few lenses with which to interpret something as extraordinary as 5-MeO-DMT experiences. And I believe this comes at a great cost to people’s sanity and epistemic rationality.

What Are Leo’s Background Assumptions?

In the pre-retreat video Leo says that his core teachings (and what he attempts to realize on his own self) are: (1) you are literally God, (2) there is nothing but consciousness – God is infinite consciousness, (3) everything is states of consciousness – everything at all times is a different state of consciousness, (4) you are love – and love is absolute – this is all constructed out of love – fear is just fear of aspects of yourself you have disconnected from, (5) you have no beginning and no end, (6) you should be radically open-minded. Then he also adds that physical and mental health issues are just manifestations of your resistance to realizing that you are God.

What Are My Background Assumptions?

Personal Identity

I am quite sympathetic to the idea of oneness, which is also talked about with terms like nonduality and monopsychism. In philosophical terminology, which I find to be more precise and rigorous, this concept goes by the name of Open Individualism – the belief that we are all one single consciousness. I have written extensively about Open Individualism in the past (e.g. 1, 2, 3), but I would like to point out that the arguments I’ve presented in favor of this view are not based on direct experience, but rather, on logical consistency from background assumptions we take for granted. For instance, if you assume that you are the same subject of experience you were a second ago, it follows that you can exist in two points in space-time and still be the same being. Your physical configuration is different than a few seconds ago (let alone a decade), you have slightly different memories, the neurons active are different, etc. For every property you point out as your “identity carrier” I can find a counter-example where such carrier changes a little while you still remain the same subject of experience. Add to that teleportation, fission, fusion, and gradual replacement thought experiments and you can build a framework where you can become any other arbitrary person without a loss of identity. These lines of argumentation coupled with the transitivity of identity can build the case that we are indeed all one to begin with.

But realize that rather than saying that you can grasp this (potential) truth directly from first person experience, I build from agreed upon assumptions to arrive at an otherwise outlandish view. Understanding the argument does not entail “feeling we are all one”, and neither does feeling we are all one entails understanding the arguments!

Indirect Realism About Perception

There is a mind-independent world out there and you never get to experience it directly. In some sense, we each live in a private skull-bound world-simulation that tracks the fitness-relevant features of our environment. Hence, during meditation, dreaming, or psychedelic states you are not accessing any sort of external reality directly, but rather, exploring possible configurations and qualities of your inner world-simulation. This is something that Leo may implicitly not realize. In particular, interpreting 5-MeO-DMT experiences through direct realism (also called naïve realism – the view that you experience the world directly through your senses) would make you think that you are literally merging with the entire cosmos on the drug. Whereas interpreting those experiences with indirect realism merely entails that your inner boundaries are dissolving. In other words, the partitions inside your world-simulation are what implements the feeling of the self-other duality. And since 5-MeO-DMT dissolves inner boundaries, it feels as though you are becoming one with your surroundings (and the rest of reality).

Physicalism and Panpsychism

An important background assumption is that the laws of physics accurately describe the behavior of the universe. This is distinct from materialism, which would also posit that all matter is inherently insentient. Physicalism merely says that the laws of physics describe the behavior of the physical, but leaves its intrinsic nature as an open question. Together with panpsychism, however, physicalism entails that what the laws of physics are describing is the behavior of consciousness.

Tyranny of the Intentional Object

We tend to believe that what makes us happy is external to us, while in reality happiness is a state of consciousness triggered by external circumstances. Our minds lead us to believe otherwise for evolutionary reasons.

Valence Structuralism

What makes an experience feel good or bad is not its semantic content, its computational use, or even whether the experience is self-reinforcing or not. What makes experiences feel good or bad is their structure. In particular, a very promising idea that will come up below is that highly symmetrical states of consciousness are inherently blissful, such as those we can access during orgasm, meditation, psychedelics, or even just good food and a hug. Recall that 5-MeO-DMT dissolves internal boundaries, and this is indicative of increased inner symmetry (where the boundaries themselves entail symmetry breaking operations). Thus, an exotic state of oneness is blissful not because you are merging with God, but “merely” because it has a higher degree of symmetry and therefore it’s valence is higher than what we can normally experience. In particular, the symmetry I’m talking abut here may be an objective feature of experiences perhaps even measurable with today’s neuroimaging technology.

There are additional key background philosophical assumptions, but the above are enough to get us started analyzing Leo’s 5-MeO-DMT journey from a different angle.


The Video

[Video descriptions are in italics whereas my commentary is bolded.]

For the first 8 minutes or so Leo explains that people do not really know that there are many levels of enlightenment. He starts out strong by claiming that he has reached levels of enlightenment that nobody (or perhaps just a few people) have ever reached. More so, while he agrees with the teachings of meditation masters of the past, he questions the levels of awakening that they had actually reached. It takes one to know one, and he claims that he’s seen things far beyond what previous teachers have talked about. More so, he argues that people simply have no way of knowing how enlightened their teachers are. People just trust books, gurus, teachers, religious leaders, etc. about whether they are “fully” enlightened, but how could they know for sure without reaching their level, and then surpassing them? He wraps up this part of the video by saying that the only viable path is to go all the way by yourself – to dismiss all the teachers, all the books, and all the instructions and see how far you can go on your own when genuinely pursuing truth by yourself.

With this epistemological caveat out of the way, Leo goes on to describe his methodology. Namely, he embarked on a quest of taking 5-MeO-DMT at increasing doses every day for 30 days in a row.leo_10_05

At 10:05 he says that within a week of this protocol he started reaching levels of awakening so elevated that he realized he had already surpassed every single spiritual teacher that he had ever heard of. He started writing a manifesto explaining this, claiming that even the most enlightened humans are not truly as awake as he became during that week. That it had became “completely transparent that most people who say they are awake or teach awakening are not even 1% awake”. But he decided not to go forward with the manifesto because he still values the teachings of spiritual leaders, whom according to him are doing a great service to mankind. He didn’t want to start, what he called, a “nonduality war” (which is of course a fascinating term if you think about it).

The main thing I’d like to comment here is that Leo is never entirely clear about what makes an “awakening experience” authentic. From what I gather (and from what comes next in the video) we can infer that the leading criteria consists of a fuzzy blend of experience of certainty, feeling of unity, and sense of direct knowing coupled together. To the extent that 5-MeO-DMT does all of these things to an extraordinary degree, we can take Leo on his words that he indeed experienced states of consciousness that feel like awakening that are most likely inaccessible to everyone who hasn’t gone through a protocol like his. What is still unclear is how exactly the semantic contents of these experiences are verified by means other than intuition. We will come back to that.

At 16:00 he makes the distinction between awakening as merely “cessation”, “nothingness”, “emptiness”, “the Self”, or that “you are nothing and everything” versus what he has been experiencing. He agrees that those are true and worthy realizations, but he claims that before his experiences, these understandings were still only realized at a very “low level”. Other masters, he claims, may care about ending suffering, about peace, about emptiness, and so on. But that nobody seems to truly care about understanding reality (because otherwise they would be doing what he’s doing). He rebukes possible critics (arguably of the Zen variety) who would say that “understanding is a function of the mind” so the goal shouldn’t be to understand. He asserts that no, based on his lived experience, that consciousness is capable of “infinite understanding”.

Notwithstanding the challenges posed by ultrafinitism, I am also inclined to believe Leo that he has experienced completely new varieties of “understanding”. In my model of the mind, understanding something means to have the ability to render it in your world-simulation in a particular kind of way that allows you to see it from every possible angle you have access to. On 5-MeO-DMT, as we will see to a greater extent below, a certain new set of projective operations get unlocked that allow you to render information from many, many more points of view at the same time. It is unclear whether this is possible with meditation alone (in personal communication, Daniel Ingram said yes) but it is certainly extraordinarily rare for even advanced meditators to be able to do this. So I am with Leo when it comes to describing “new kinds of understandings”. But perhaps I am not on board when it comes to claiming that the content of such understandings is an accurate rendering of the structure of reality.

At 18:30 Leo asserts that what happened to him is that over the course of the first week of his experiment he “completely understood reality, completely understood what God is”. God has no beginning and no end. He explains that normal human understanding sees situations from a single point of view (such as from the past to the future). But that actual infinite reality is from all sides at once: “When you are in full God consciousness, you look around the room, and you can see it from every single point of view, from an infinite number of angle and perspectives. You see that every part of the room generates and manufactures and creates every other part. […] Here when you are in God consciousness, you see it from every single possible dimension and angle. It’s not happening lilnearly, it’s all in the present now. And you can see it from every angle almost as though, if you take a watermelon and you do a cross-section with a giant knife, through that watermelon, and you keep doing cross-section, cross-section, cross-section in various different angles, eventually you’ll slice it up into an infinite number of perspectives. And then you’ll understand the entire watermelon as a sort of a whole. Whereas usually as humans what we do is we slice down that watermelon just right down the middle. And we just see that one cross-section.”

Now, this is extremely interesting. But first, it’s important to point out that here Leo might implicitly be reasoning about his experience through the lens of direct realism about perception. That is, that as he experiences this profound sense of understanding that encompasses every possible angle at once, he seems to believe that this is an understanding of his environment, of his future and past, and of reality as a whole. On the other hand, if you start out assuming indirect realism about perception, how you interpret this experience would be in terms of the instantiation of new exotic geometries of your own world-simulation. Here I must bring up the analysis of “regular” DMT (i.e. n,n-DMT) experiences through the lens of hyperbolic geometry. Indeed, regular DMT elevates the energy of your consciousness, which manifests in brighter colors, fast movement, intricate and detailed patterns, and as curved phenomenal space. We know this because of numerous trip reports from people well educated in advanced mathematics who claim that the visual symmetries one can experience on DMT (at doses above 10mg) have hyperbolic curvature (cf. hyperbolic orbifolds). It is also consistent with many other phenomena one can experience on DMT (see the Eli 5 for a quick summary). But you should keep in mind that this analysis never claims that you are experiencing directly a mind-independent “hyperspace”. Rather, the analysis focuses on how DMT modifies the geometric properties of your inner world-simulation.

Hyperbolic Geometry of DMT Experiences copy 47

Energy-complexity landscape on DMT

Hyperbolic Geometry of DMT Experiences copy 38

DMT trip progression

Intriguingly, our inner world-simulations work with projective geometry. In normal circumstances our world-simulations have a consistent set of projective points at infinity – they render the modal and amodal features of our experience in projective scenes that are globally consistent. But psychedelics can give rise to this phenomenon of “point-of-view-fragmentation“, where your experience becomes a patchwork of inconsistent projective renderings. So even on “regular” DMT you can get the profound feeling of “seeing something from multiple points of view at once”. Enhanced with hyperbolic geometry, this can cause the stark impression that you can explore “hyperspace” with a kind of “ultra-understanding”.

Looking beyond “regular” DMT, 5-MeO-DMT is yet more crazy than that. You see, even on DMT you get the feeling that you are restricted in the number of points of view from which you can see something at the same time. You can see it from many more points of view than normal, but it’s still restricted. But the extreme “smoothing” of experience that 5-MeO-DMT causes makes it so that you cannot distinguish one point of view from another. So they all blend together. Not only do you experience semantic content from “multiple points of view at once” as in DMT, but you can erase distinctions between points of view so that one’s sense of knowing arises involving a totally new kind of projective effect, in which you actually feel you can see something from “every point of view at once”. It feels that you have unlocked a kind of omniscience. This already happens on other psychedelics to a lesser extent (and in meditation, and even sober life to an even lesser extent, but still there), and it is a consequence of smoothing the geometry of your experience to such an extent that there are no symmetry-breaking imperfections “with which to orient a projective point”. I suspect that the higher “formless” jhanas of “boundless space” and “boundless consciousness” are hitting at this effect. And on 5-MeO-DMT this effect is pronounced. More so, because of the connection between symmetry and smoothness of space (cf. Geometry Through the Eyes of Felix Klein) when this happens you will also automatically be instantiating a high-dimensional group. And according to the Symmetry Theory of Valence, this ought to be extraordinarily blissful. And indeed it is.

This is, perhaps, partly what is going on in the experience that Leo is describing. Again, I am inclined to believe his description, but happy to dismiss his naïve interpretation.

indras_net

Indra’s Net

At 23:15 Leo describes how from his 5-MeO-DMT point of view he realized what “consciousness truly is”. And that is an “infinitely interconnected self-communicating field”. In normal everyday states of consciousness the different parts of your experience are “connected” but not “communicating.” But on 5-MeO, “as you become more conscious, what happens is that every point in space inter-connects with itself and starts to communicate with itself. This is a really profound, shocking, mystical experience. And it keeps getting cranked up more and more and more. You can call it omniscience, or telepathy. And it’s like the universal communication system gets turned on for the first time. Right now your conscious field is not in infinite communication with itself. It’s fragmented and divided. Such that you think I’m over here, you are over there, my computer is over here, your computer is over there…”. He explains that if we were to realize we are all one, we would then instantly be able to communicate between each other.

Here again we get extremely different interpretations of the phenomena Leo describes depending on whether you believe in direct or indirect realism about perception. As Leo implicitly assumes direct realism about perception, he interprets this effect as literally switching on an “universal communication system” between every points in reality, whereas the indirect realist interpretation would be that you have somehow interlocked the pieces of your conscious experience in such a way that they now act as an interconnected whole. This is something that indeed has been reported before, and at QRI we call this effect “network integration“. A simple way of encapsulating this phenomenon would be by saying that the cross-frequency coupling of your nervous system is massively increased so that there is seamless information and energy transfer between vibrations at different scales (to a much lesser extent MDMA also does this, but 5-MeO-DMT is the most powerful “integration aid” we know of). This sounds crazy but it really isn’t. After all, your nervous system is a network of oscillators. It stands to reason that you can change how they interact with one another by fine-tuning their connections and get as a result decoupling of vibrations (e.g. SSRIs), or coupling only between vibrations of a specific frequency (e.g. stimulants and depressants), or more coupling in general (e.g. psychedelics). In particular, 5-MeO-DMT does seem to cause a massively effective kind of fractal coupling, where every vibration can get in tune with every other vibration. And recall, since a lot of our inner world simulation is about representing “external reality”, this effect can give rise to the feeling that you can now instantly communicate with other parts of reality as a whole. This, from my point of view, is merely misinterpreting the experience by imagining that you have direct access to your surroundings.

At 34:52 Leo explains that you just need 5-MeO-DMT to experience these awakenings. And yet, he also claims that everything in reality is imaginary. It is all something that you, as God, are imagining because “you need a story to deny that you are infinite consciousness.” Even though the neurotransmitters are imaginary, you still need to modify them in order to have this experience: “I’m talking about superhuman levels of consciousness. These are not levels of consciousness that you can access sober. You need to literally upgrade the neurotransmitters in your imaginary brain. And yes, your brain is still imaginary, and those neurotransmitters are imaginary. But you still need to upgrade them nevertheless in order to access some of the things I say.”

Needless to say, it’s bizarre that you would need imaginary neurotransmitter-mimicking molecules in your brain in order to realize that all of reality is your own imagination. When you dream, do you need to find a specific drug inside your dream in order to wake up from the dream? Perhaps this view can indeed be steel-manned, but the odds seem stacked against it.

At 38:30 he starts talking about his pornography collection. He assembles nude images of women, not only to relieve horniness, but also as a kind of pursuit of aesthetics. Pictures of nude super-models are some of the most beautiful things a (straight) man can see. He brings this up in order to talk about how he then at some point started exploring watching these pictures on 5-MeO-DMT. Recollecting this brings him to tears because of how beautiful the experiences were. He states “you’ve never really seen porn until you’ve seen it on 5-MeO-DMT.” He claims that he started to feel that this way he really felt that it is you (God) that is beautiful, which is manifested through those pictures.

A robust finding in the psychology of sexual attraction is that symmetry in faces is correlated with attractiveness. Indeed, more regular faces tend to be perceived as more beautiful. Amazingly, you can play with this effect by decorating someone’s face with face-paint. The more symmetrical the pattern, the more beautiful the face looks (and vice-versa). Arguably, the effect Leo is describing where people who are already beautiful become unbelievably pretty on 5-MeO-DMT involves embedding high-dimensional symmetries into the way you render them in your world-simulation. A lesser, and perhaps more reliable, version of this effect happens when you look at people on MDMA. They look way more attractive than what they look like sober.

Leo then brings up (~41:30) that he started to take 5-MeO-DMT on warm baths as well, which he reassures us is not as dangerous as it sounds (not enough water to drown if he experiences a whiteout). [It’s important to mention that people have died by taking ketamine on bath tubs; although a different drug, it is arguably still extremely dangerous to take 5-MeO-DMT alone on a bathtub; don’t do it]. He then has an incredible awakening surrendering to God consciousness in the bathtub, on 5-MeO-DMT, jerking off to beautiful women in the screen of his laptop. He gets a profound insight into the very “nature of desire”. He explains that it is very difficult to recognize the true nature of desire while on a normal level of consciousness because our desires are biased and fragmented. When “your consciousness becomes infinite” those biases dissolve, and you experience desire in its pure form. Which according to his direct experience turned out to be “desire for God, desire for myself”. And this is because you are, deep down “infinite love”. When you desire a husband, or sex, or whatever, you are really desiring God in disguise. But the problem is that since your path to God is constrained by the form you desire, your connection to God is not stable. But once you have this experience of complete understanding of what desire is, you finally get your desire fully quenched by experiencing God’s love.

This is a very deep point. It is related to what I’ve sometimes called the “most important philosophical question“, which is: is valence a spiritual phenomenon or spirituality a valence phenomenon? In other words, do we find experiences of God blissful because they have harmony and symmetry, or perhaps is it the other way around, where even the most trivial of pleasures, like drinking a good smoothy, feels good because it temporarily “gets you closer to God”? I lean towards the former, and that in fact mystical experiences are so beautiful because they are indeed extremely harmonious and resonant states of consciousness, and not because they take you closer to God. But I know very smart people who can’t decide between these views. For example, my friend Stuart Garvagh writes: 

What if the two options are indistinguishable? Suppose valence is a measure of the harmony/symmetry of the object of consciousness, and the experience of “Oneness” or Cosmic Consciousness is equivalent to having the object of consciousness be all of creation (God‘s object), a highly symmetrical, full-spectrum object (full of bliss, light, love, beingness, all-knowledge, empty of discernible content or information). All objects of consciousness are distortions (or refractions, or something) of this one object. Happiness is equivalent to reducing or “polishing-out” these distortions. Thus, what appears to be just the fact of certain states being more pleasant than others is equivalent to certain states being closer to God‘s creation as a whole. Obviously this is all pure speculation and just a story to illustrate a point, but I could see it being very tough to tease apart the truth-value of 1 and 2. Note: I’m fairly agnostic myself, but lean towards 2 (bliss is the perfume of “God realizing God” or the subject of experience knowing Itself). I would very much love to have this question answered convincingly!

At 50:00 Leo says that “everything I’ve described so far is really a prelude to the real heart of awakening, which is the discovery of love. […] I had already awakened to love a number of times, but this was deeper. By the two week mark the love really started to crack open. Infinite self-love. You are drowning on this love.” He goes on to describe how at this point he was developing a form of telepathy that allowed him to communicate with God directly (which is, of course, a way of talking to himself as he is God already). It’s just a helpful way to further develop. And what God was showing him was how to receive self-love. It was so much at first he couldn’t handle it. And so he went through a self-purification process.

An interesting lens with which to interpret this experience of purification is that of neural annealing. Each 5-MeO-DMT experience would be making Leo’s nervous system resonate in ways in new ways, slowly writing over previous patterns and entraining the characteristic high-symmetry patterns of the state. Over time, the nervous system adjusts its weights in order to be able to handle that resonance without getting its patterns over-written. In other words, Leo has been transforming his nervous system into a kind of high-valence machine, which is of course very beneficial for intrinsic feelings of wellbeing (though perhaps detrimental to one’s epistemology).

55:00: He points out that unlike addictive drugs, he actually had to push himself very hard to continue to take 5-MeO-DMT everyday for 30 days. He stopped wanting to do it. The ego didn’t want it. And yes, it was pleasurable once he surrendered on every session, but it was difficult, heavy spiritual work. He says that he could only really do this because of years of practice with and without psychedelics, intense meditation, and a lot of personal development. And because of this, he explains his 5-MeO experiences felt like “years of spiritual work condensed into a single hour.” He then says that God will never judge you, and will help you to accept whatever terrible things you’ve done. And many of his subsequent trips were centered around self-acceptance. 

Following the path of progressive neural annealing, going deeper and deeper into a state of self-acceptance can be understood as a deeper harmonization of your nervous system with itself.

At 1:01:20, Leo claims to have figured out what the purpose of reality truly is: “Reality is a contest for who can love who more. That’s really what life is about when you are fully conscious. […] Consciousness is a race for who can love who more. […] An intelligent fully conscious consciousness would only be interested in love. It wouldn’t be interested in anything else. Because everything else is inferior. […] Everything else is just utter silliness!”

I tend to agree with this, though perhaps not in an agentive way. As David Pearce says: “the pleasure-pain axis discloses the universe’s intrinsic value function.” So when you’ve annealed extremely harmonious patterns and do not get distracted by negative emotion, naturally, all there is left to do is maximize love. Unless we mess up, this is the only good final destiny for the cosmos (albeit perhaps it might take the form of a Hedonium shockwave, which at least in our current human form, sound utterly unappealing to most people).

1:06:10 “[God’s love] sparks you to also want to love it back. You see, it turns into a reciprocal reaction, where it is like two mirrors that are mirroring light between each other like a laser beam that is bouncing between two mirrors. And it’s bouncing back and forth and back and forth. And as it bounces back and forth it becomes more and more concentrated. And it strengthens. And it becomes more coherent. And so that’s what started happening. At first it started out as just a little game. Like ‘I love you, I love you, I love you’. A little game. It sounds like it’s almost like childish. And it sort of was. But then it morphed from being this childish thing, into being this serious existential business. This turned into the work. This was the true awakening. Is that with the two mirrors, you know, first it took a little while to get the two mirrors aligned. Because you know if the two mirrors are not perfectly aligned, the laser beam will kind of bounce back and forth in different directions. It’s not going to really concentrate. So that was happening at first. […] The love started bouncing back and forth between us, and getting stronger and stronger. […] Each time it bounces back to me it transforms me. It opens me up deeper. And as it opens me up deeper it reveals blockages and obstacles to my capacity to love.”

Now this is a fascinating account. And while Leo interprets it in a completely mystical way, the description also fits very well an annealing process where the nervous system gets more and more fine-tuned in order to be able to contain high levels of coherent energy via symmetry. Again, this would be extremely high-valence as a consequence of the Symmetry Theory of Valence. Notice that we’ve talked about this phenomenon of “infinite mirrors” on psychedelics since 2016 (see: Algorithmic Reduction of Psychedelic States).

At ~1:09:30 he starts discussing that at this point he was confronted by God about whether he was willing to love the holocaust, and rape, and murder, and bullies, and people of all sorts, even devil worshipers. 

Two important points here. First, it is a bit ambiguous whether Leo here is using the word “love” in the sense of “enjoyment” or in the sense of “loving-kindness and compassion”. The former would be disturbing while the latter would be admirable. I suppose he was talking about the latter, in which case “loving rape” would refer to “being able to accept and forgive those who rape” which indeed sounds very Godly. This radical move is explored in metta (loving-kindness) meditation and it seems healthy on the whole. And second: Why? Why go through the trouble of embracing all the evil and repulsive aspects of ourselves? One interpretation here, coming back to the analysis based on neural annealing, is that any little kink or imperfection caused by negative emotion in our nervous system will create slight symmetry breaking effects on the resonance of the entire system as whole. So after you’ve “polished and aligned the mirrors for long enough” the tiny imperfections become the next natural blockage to overcome in order to maximize the preservation of coherent energy via symmetry.

~1:12:00 Leo explains that the hardest thing to love is your own self-hatred. In the bouncing off of the love between you and God, with each bounce, you find that the parts you hate about yourself reflect an imperfect love. But God loves all of you including your self-hatred. So he pings you about that. And once you can accept it, that’s what truly changes you. “Because when you feel that love, and you feel how accepting it is, and how forgiving it is of all of your evil and of all of your sins… that’s the thing that kills you, that transforms you. That’s what breaks your heart, wide open. That’s what gets you to surrender. That’s what humbles you. That’s what heals you.” Leo then explains that he discovered what “healing is”. And it is “truth and love”. That in order to heal anyone, you need to love them and accept them. Not via sappy postcards and white lies but by truth. He also states that all physical, mental, and spiritual ailments have, at their root, lack of love.

If love is one of the cleanest expressions of high-valence symmetry and resonance, we can certainly expect that inundating a nervous system with it will smooth and clean its blockages, i.e. the sources of neural dissonance. Hence the incredible power of MDMA on healing nervous systems in the short-term. Indeed, positive emotion is itself healing and enhances neural coherence. But where I think this view is incomplete is in diagnosing the terrible suffering that goes on in the world in terms of a lack of love. For instance, are cluster headaches really just the result of lack of self-love? In here must bring back the background assumption of physicalism and make a firm statement that if we fall into illusion about the nature of reality we risk not saving people (and sentient beings more generally) who are really in the depth of Hell. Just loving them without taking the causally-relevant physical action to prevent their suffering is, in my opinion, not true love. Hence the importance of maintaining a high level of epistemic rigor: for the sake of others. (See: Hell Must Be Destroyed).

1:22:30 Leo explains that in this “love contest” with God of bouncing off love through parallel mirrors the love became so deep that for the first time in his life he felt the need to apologize: “I’m sorry for not loving more.” He goes into a sermon about how we are petty, and selfish, etc. and how God loves us anyway. “Real love means: I really love you as you are. And I don’t need anything from you. And especially all those things that you think I want you to change about you, I don’t need you to change. I can accept them all exactly as they are. Because that’s love. And when you realize THAT, that’s what transforms you. It is not that God says that he loves you. He is demonstrating it. It’s the demonstration that transforms you.” Leo expresses that he was then for the first time in his life able to say “thank you” sincerely. Specifically, “thank you for your love”: “This is the point at which you’ve really been touched by God’s love. And at this point you realize that that’s it, that’s the point, that’s the lesson in life. That’s my only job. It’s to love.” And finally, that for the first time in his life he was able to say “I love you” and truly mean it. “And you fall in love with God… but it doesn’t end there.”

An interesting interpretation of the felt-sense of “truly meaning” words like “I’m sorry”, “thank you”, and “I love you” is that at this point Leo has really deeply annealed his nervous system into a vessel for coherent energy. In other words, at this point he is saying and meaning those words through the whole of his nervous system, rather than them coming from a fragmented region of a complex set of competing internal family systems in a scattered way. Which is, of course, the way it usually goes.

1:35:30 Leo explains that at this point he started going into the stage of being able to radiate love. That he was unable to radiate love before. “I love that you are not capable of love. I love that. And when that hits you, that’s what fills you with enough love to overcome your resistance to love that next level thing that you couldn’t love.” Then at ~ 1:38:00 it gets really serious. Leo explains that so far he was just loving and accepting past events and people. But he was then asked by God whether he would be willing to live through the worst things that have happened and will happen. To incarnate and be tortured, among many other horrible things. And that’s what true love really means. “When you see a murder on the TV, you have to realize that God lived through that. And the only reason he lived through that is because it loved it.”

I do not understand this. Here is where the distinction between the two kinds of senses of the word “love” become very important. I worry that Leo has annealed to the version of love with the meaning of “enjoyment” rather than “loving-kindness and compassion”. Because a loving God would be happy to take the place of someone who went through Hell. But would a loving God send himself to Hell if nobody had to in the first place? That would just create suffering out of nothing. So I am confused about why Leo would believe this to be the case. It’s quite possible that there are many maxima of symmetry in the nervous system you can achieve with 5-MeO-DMT, and some of them are loving in the sense of compassionate and others are crazy and would be willing to create suffering out of nothing from a misguided understanding of what love is supposed to be. Again, handle Plutonium with caution.

1:43:00 Leo started wondering “what is reality then?” And the answer was: “It’s infinite consciousness. Infinite formless consciousness. So what happens was that my mind in my visual field as I was in that bathtub. My mind and my visual field focused in on empty space, and I sort of zoomed into that empty space and realized that that empty space is just love”. He then describes a process where his consciousness became more and more concentrated and absorbed into space, each dot of consciousness branching out into more and more dots of consciousness, turning into the brightest possible white light. But when he inquired into what was that white light he kept seeing that there was no end to it, and rather, that each point was always connected to more points. Inquiring further, he would get the response that at the core, reality is pure love. That it wouldn’t be and couldn’t be any other way.

The description sounds remarkably close to the formless jhanas such as “boundless space” and “boundless consciousness”. The description itself is extremely reminiscent of an annealing process, reaching a highly energized state of consciousness nearly devoid of information content and nearly perfectly symmetrical. The fact that at this incredibly annealed level he felt so much love supports the Symmetry Theory of Valence.

147:28 – And after Leo realizes that “Of course it is love!” he says that’s when the fear comes: “Because then what you realize is that this is the end. This is the end of your life. You are dead. If you go any further you are dead. Everything will disappear. Your family, your friends, you parents, all of it is completely imaginary. And if you stop imagining it right now, it will all end. If you go any further into this Singularity, you will become pure, formless, infinite, love for ever, loving itself forever. And the entire universe will be destroyed as if it never existed. Complete nothingness. Complete everythingness. You will merge into everyone.”

This sounds like the transition between the 6th and 7th Jhana, i.e. between “boundless consciousness” and “nothingness”. Again, this would be the result of further loss of information via an annealing process, refining the symmetry up to that of a “point”. Interestingly, Mike Johnson in Principia Quallia points out that as symmetry approaches an asymptote of perfection you do get a higher quality of valence but at the cost of reduced consciousness. This might explain why you go from “the brightest possible love” to a feeling of nothingness at this critical transition.

1:48:25: “…You will merge into everyone. Your mother, your father, your children, your spouse, Hitler, terrorists, 9/11, Donald Trump, rape, murder, torture, everything will become pure infinite love, merging completely into itself, there will be no distinction between absolutely anything, and that will be the end. And you will realize what reality is. Infinite consciousness. Love. God. And you will realize that everything in your life from your birth to this point has just been some imaginary story. A dream that was design to lead you to pure absolute infinite love. And you will rest in that love forever. Forever falling in love with yourself. Forever making love to yourself. Forever in infinite union. With every possible object that could ever exist. Pure absolute, omnipotent, omniscient, perfect, intelligent, consciousness. Everything that could ever possibly be, is you. And THAT is awakening. When you are this awake, you are dead. And you have no desire for life. There is no physical existence. There is no universe. Nothing remains. Your parents, and your spouse, and your children, they don’t stay back and keep living their lives, enjoying their life without you while your body drops dead. No, no, no, no, no. This is much more serious than that. If you do this. If you become infinite love, you will take everybody with you. There will not be anybody left. You will destroy the entire universe. Every single sentient being will become you. They will have no existence whatsoever. Zero. They will die with you. They will all awaken with you. It’s infinite awakening. It’s completely absolute. There will not be anything left. You will take the entire universe with you. Into pure oneness. THAT’S awakening.”

This is not the first time I hear about this kind of experience. It certainly sounds extraordinarily scary. Though perhaps a negative utilitarian would find it to be the ultimate relief and the best of all possible imaginable outcomes. With the human survival instinct, and quite possibly a body fully aroused with the incredible power of 5-MeO-DMT, this is bound to be one of the most terrifying feelings possible. It’s quite likely that it may be one element of what makes “bad 5-MeO-DMT experiences” so terrifying. But here we must recall that the map is not the territory. And while an annealing process might slowly write over every single facet of one’s model of reality and in turn making them part of a super-cluster of high-dimensional resonance that reflects itself seemingly infinitely, doing this does not entail that you are in fact about to destroy the universe. Though, admittedly, it will surely feel that way. Additionally, I would gather that were it possible to actually end the universe this way, somebody, somewhere, in some reality or another, would have already done so. Remember that if God could be killed, it’d be dead already.

1:52:01: “And I didn’t go there! As you can tell, since I’m still sitting here. I’m not there. I was too afraid to go there. And God was fine with it. It didn’t push me. But that’s not the end of the story! It’s still just the beginning.” He then goes on to explain that a part of him wanted to do it and another part of him didn’t want to. He says it got really loopy and weird; this really shook him. That God was beckoning him to go and be one forever, but he was still ambivalent and needed some time to think about it. He knew it would make no difference, but he still decided to ‘make preparations’ and tell his family and friends that he loves them before moving forward with a final decision to annihilate the universe. By the time he had done that… he had stopped taking 5-MeO-DMT: “The experiences had gotten so profound and so deep… this was roughly the 25th or 27th day of this whole 30 day process. I swore off 5-MeO-DMT and said ‘Ok I’m not doing any more of this shit. It’s enough'”. He explains that by this time the drug was making him feel infinite consciousness when waking up (from sleep) the next day. He felt the Singularity was sucking him into it. It felt both terrifying and irresistible. Every time he would go to sleep it would suck him in really strongly, and he kept resisting it. He would wake up sweaty and in a panic. He was tripping deeper in his sleep than in the bathtub. He couldn’t sleep without this happening, and it kept happening for about 5 days. “I just want to get back to normal. This is getting freaky now.” 

I’ve heard this from more than a couple people. That is, that when one does 5-MeO-DMT enough times, and especially within a short enough period of time, the “realizations” start to also happen during sleep in an involuntarily way. One can interpret this as the annealing process of 5-MeO-DMT now latching on to sleep (itself a natural annealing process meant to lessen the technical debt of the nervous system). Even just a couple strong trips can really change what sleep feels like for many days. I can’t imagine just how intense it must have been for Leo after 25 days straight of using this drug.

2:01:40 – Leo explains that when he was dozing off with a blanket on his living room (terrified of sleeping on his bed due to the effect just described) he experienced a “yet deeper awakening” which involved realizing that all of his previous awakenings were just like points and that the new one was like a line connecting many points. “Everything I’ve said up to this point were just a single dimension of awakening. And then what I broke through to is a second dimension. A second dimension of awakening opened up. This second dimension is completely unimaginable, completely indescribable, cannot be talked about, cannot be thought about. And yet it’s there. In it, are things that are completely outside of the physical universe that you cannot conceive or imagine.” He goes on to explain that there are then also a third, fourth, fifth, etc. dimensions. And that he believes there is an infinite number of them. He barely even began to explore the second dimension of awakening, but he realized that it goes forever. It kept happening, he had intense emotional distress and mood swings. But gradually after five more days it subsided, and he started to be able to sleep more normally. “And I’ve been working to make sense of all of this for the last couple of weeks. So that’s what happened.”

Alright, this is out of my depth and I do not have an interpretation of what this “second dimension of awakening” is about. If anyone has any clue, please leave a comment or shoot me an email. I’m as as confused as Leo is about this.

~2:05:00 – Leo confesses he does not know what would happen if he went through with joining the Singularity and mentions that it sounds a bit like Mahasamādhi. He simply has not answers at this point, but he asserts that the experience has made him question the extent of the enlightenment of other teachers. It also has made him more loving. But still, he feels frustration: “I don’t know what to do from here.”

And neither do I. Do you, dear reader?

Postscript: In the last 10 minutes of the video Leo shares a heart warming message about how reality is, deep down, truly, “just love” and that him saying this may be a seed that will blossom into you finding this out for yourself at some point in the future. He ends by cautioning his audience to not believe as a matter of fact that this is the path for everyone. He suggests that others should just use his examples from his own journey as examples rather than an absolute guide or how-to for enlightenment. He asks his audience to make sure to question the depth of their own awakening – to not believe that they have reached the ultimate level. He admits he has no idea whether there is an ultimate level or not, and that he still has some healing to do on himself. He remains dissatisfied with his understanding of reality.


Thank you for reading!

THE END

Making Amazing Recreational Drug Cocktails

Californidine

Imagine that you were tasked with creating a molecule to represent the spirit of California. I think that I would just glue together two MDMA molecules and call it a day.

1200px-Californidine.svg

Californidine

It turns out Californidine is indeed a real molecule, named after the California Poppy. I am still wrapping my head around the fact that Californidine can be described as two MDMA molecules sharing the nitrogen atom and with the end of the carbon chain of each MDMA molecule bonded at the 2-position of the benzene ring of the other one (minus a hydrogen atom). Interestingly, this compound has no psychedelic or empathogenic action. At best, it can be described as a very mild and unreliable relaxing agent of “herbal strength” akin to the active ingredients of chamomile, valerian, or ashwagandha. So, joining two powerful heart-openers gives rise to a mild sleep-inducer? Perhaps this is a metaphor for something.

californidine_mdma_

Californidine and MDMA

But that’s not what I want to talk to you about today. While gluing together psychoactive molecules may not have a (cartoonishly) desirable additive effect, doing so does express the spirit of what I want to propose today. And that is the impulse to use a creative and fun approach to drug design, letting your imagination run wild to avoid prematurely discarding one’s crazy ideas.

Notable Leads for Great Drug Combos

Over the last 10 years I’ve read many (many!) trip reports and have talked to hundreds of experienced psychonauts (see also: r/replications). It is largely thanks to a subset of these psychonauts, which for lack of a better term could be described as the subset of rational psychonauts, that I’ve been able to assemble empirically testable models for psychedelic phenomenology (some examples: Algorithmic Reduction of Psychedelic States, Hyperbolic Geometry of DMT Experiences, Quantifying Bliss, How to Secretly Communicate with People on LSD, etc.). Although my focus has largely been on the effects of individual drugs, I’ve become very cognizant of the fact that drug combinations can produce effects not accessible with individual substances. In other words, when it comes to mixing psychoactive substances, the sum is more often than not different from the sum of its parts. Some of these effects seem extremely significant both from a scientific and a philosophical point of view.

But first, an important disclaimer: mixing drugs is dangerous and you should never do it unless you really know what you are doing. The pile of celebrity deaths caused by multiple drug intoxication is only scratching the surface. Indeed, there are many combinations of drugs that are deadly even when the individual drugs taken on their own are relatively safe. For example, while 5-MeO-DMT is relatively safe when vaporized (save for egregiously negligent uses of the drug and the occasional drowning in one’s own vomit), taking 5-MeO-DMT orally in combination with an MAOI leads to extremely toxic reactions, such as severe hypertensive symptoms, overheating, and serotonin syndrome. Don’t do it. As a very rough guide for how mixtures of psychoactives behave, study the chart below.

Combo_2

Welcome to the practice of combining drugs. You may die. (source)

That said, just as drug combinations have a dangerous side, they also likely harbor hidden gems that are very safe, enjoyable, and mind-expanding in ways inaccessible via single drugs. As a general overview, some examples of the possible benefits of drug combinations include: (1) Enhanced euphoria, e.g. see speedball which is massively euphoric but also very dangerous, (2) reduced psychological discomfort (e.g. anxiolytics with psychedelics), (3) uniquely interesting effects, e.g. LSD + MDMA (see below), and (4) reduced physical side-effects and medical risks, e.g. calcium blockers to reduce MDMA neurotoxicity, 5HT2B antagonists to reduce cardiotoxicity of psychedelics, etc. as we’ll discuss. In addition, it is worth mentioning that from a therapeutic point of view, we also have the “more dakka effect“, where some conditions only respond to combining enough drugs (e.g. oncology). It’s possible chronic pain or severe depression may legitimately require multiple drugs to be adequately dealt with. Now let us examine in more detail some particularly interesting categories of drug combinations:

Psychedelics + Anxiolytics: According to many reports, phenibut in small doses seems to significantly reduce the anxiety that comes up on psychedelics. I am ambivalent about sharing this information given the fact that phenibut can become a huge problem for some people, but I think that on the whole it is wise for people to know that an over-the-counter “nootropic” can actually help avoid fear, discomfort, and panic attacks during a psychedelic experience.

Cannabis + Psychedelics: I generally find two kinds of psychedelic drug users. Those who cannot think of having a psychedelic trip without at some point smoking a joint, vaping, or eating a cannabis edible. And then those who would never dare to combine the two because they once had a terrifying experience with the combo. Interestingly, some of the people I’ve met over the years who seem to be able to easily handle massive doses of psychedelics (e.g. 500 micrograms of acid) respond terribly to weed, and especially badly if they are already tripping. Cannabis both modifies and potentiates psychedelic states of mind. It has a tendency to make the experience more conceptual rather than sensory or mystical. The combination also greatly increases the probability of getting stuck in time loops.

Empathogens + Psychedelics: One of the best descriptions of MDMA + LSD (also called candy-flipping) that I’ve found comes from Steven Lehar (emphasis added):

Under LSD and ecstasy I could see the flickering blur of visual generation most clearly. And I saw peculiar ornamental artifacts on all perceived objects, like a Fourier representation with the higher harmonics chopped off. LSD by itself creates sharply detailed ornamental artifactslike a transparent overlay of an ornamental lattice or filigree pattern superimposed on the visual scene, especially in darkness. Ecstasy smooths out those sharp edges and blurs them into a creamy smooth rolling experience. I would sometimes feel some part of my world suddenly bulging out to greater magnification, like a fish-eye lens distortion appearing randomly in space, stretching everything in that portion of space like a reflection in a funhouse mirror.

– Steven Lehar (The Phenomenal Character of LSD + MDMA)

Not everyone responds well to this combination, and given the nature of these substances, it seems likely that the dosages and the relative timing have a large influence on how the experience develops. I’ve heard three relatively “established” ways in which people use this combination. First, you have the school that says that you should take the MDMA at or slightly after the peak of the effects of LSD, that is 4-4:30h after taking it. The reasoning here is that you don’t want to be caught coming down from the MDMA while still having a long time to go on LSD since the acid could enhance the feelings of the comedown. The delayed gratification also pays-off by giving you several hours to face the problems you want to solve unaided and see how far you can get before the mood boost of MDMA gives you the determination to be contented with it.

The second school of thought about candy-flipping says that the biggest factor in how psychedelic experiences turn out is how they start. So what you want to do is take the MDMA 1 to 1:30 hours before the acid. This way, you only embark upon the inner journey when you are already in a really, really good chill state of mind. Some people report that the acid picks up the empathogenic quality of the state, amplifies it, and carries it on for much longer than if you had only taken MDMA alone.

There are many proponents and detractors to both of these schools. What I’ve seen more or less everyone agree on is to avoid taking substantial doses of LSD and MDMA (e.g. 200micrograms LSD + 120mg MDMA) at the same time. Apparently this is simply just too overwhelming and synergistic to be enjoyable, often causing a lot of nausea and palpitations.

The third school, however, is to take only a small dose of both at the same time. Say, 35micrograms LSD and 35mg MDMA. This apparently is an extremely positive combination. The experience is not mild due to the synergy, and it seems to provide an open, creative, level-headed mindset for many hours without much of a comedown or hangover. As with everything here, your mileage may vary.

Psychedelics + Dissociatives: Psychedelics and dissociatives have profound non-linear mixing effects. According to multiple sources, the right combination of LSD, Ketamine, and THC can give rise to a “free-wheeling hallucination“. This is a state of consciousness in which you gain a great degree of conscious control over the contents of the hallucinated world, so that you can project your will by saying “let there be a chair in front of me” and you will see it manifest in exquisite detail. You can rotate, translate, invert, fibrate, and project the chair in any way you want, as if you were now able to use your brain as a very general game engine of consciousness. That said, even when this doesn’t happen, the combination of psychedelics and dissociatives is ridiculously synergistic. People report getting stuck in extremely energetic time-loops akin to those caused by psychedelics and cannabis, but more powerful (cf. trip report of DMT + nitrous oxide). Steven Lehar calls the effect where the presence of a psychedelic changes the quality of a dissociative as “dissociative coloring”. I’ve been amazed at the fact that there is no mistaking when someone has previously experienced LSD and nitrous together. You don’t get reactions like “it didn’t do much for me”. This combo usually has a special place in the memory of a person who has experienced it. Eyes brighten, curiosity sparks. I’ve been asked on multiple occasions “what do you think is going on with the strange synergy between LSD and nitrous?” Now, 5-MeO-DMT and DMT are very different, and the LSD + nitrous state seems to have some resemblance with the 5-MeO-DMT state. They share that strange feeling of becoming a kind of saturated resonance box. The feeling is one of becoming a vessel full of coordinated and coherent vibrations that unearth and dissolve internal boundaries and blockages. The process inherently blocks your ability to conceptualize in a dualistic way. The cognitive content of the state is better captured by a huge blinking sign that reads “THIS, THIS, THIS” on repeat rather than the more usual “that thing over there connected to this over here, modulated by what happens there” kind of cognitive state we are more familiar with. DMT on its own is very different than this, in that the mental formations and patterns of binding that emerge are extremely specific, detailed, and irreducibly complex. Not so on the upper ranges of the dissociative and psychedelic cocktail, where the resonance is profound and the asymmetries needed to store complex information are constantly smoothed out by the ongoing full-body bath of reverb. (cf. Neural Annealing).

Dissociatives + Empathogens: According to several trip reports and credible personal communications, taking ketamine while on MDMA can bring back “the magic” that one only ever experienced with MDMA the first few times using it. Also MDMA and nitrous have profound research-worthy synergy.

Potentiation: Shulgin reported that substances that don’t feel psychedelically active on their own may nonetheless potentiate the effects of other psychedelics. For instance:

(with 160 mg of MDPR followed at 2h by 100μg LSD) This proved to be almost too intoxicating, and a problem arose that had to have a solution. The entire research group was here, and all were following this same regimen. Two hours into the second half of the experiment a telephone call came that reminded me of a promise I had made to perform in a social afternoon with the viola in a string quartet. Why did I answer the phone? My entire experience was, over the course of about 20 minutes, pushed down to a fragile threshold, and I drove about 10 minutes to attend a swank afternoon event and played an early Beethoven and a middle Mozart with an untouched glass of expensive Merlot in front of me. I could always blame the booze. I declined the magnificent food spread, split, and returned to my own party. Safely home, and given 20 more minutes, I was back into a rolling +++ and I now know that the mind has a remarkable ability to control the particular place the psyche is in. 

(Entry on MDPR, from PIHKAL)

More common than the above, ayahuasca is intrinsically a drug combo primarily of the potentiation kind. As mentioned before, cannabis not only alters but also potentiates the effects of psychedelics. It is worth mentioning there is a community of people who believe that noopept (a cholinergic nootropic, see below) can potentiate MDMA. While there is some evidence that MDMA is itself mildly cholinergic– and thus provides a sense of mental clarity in addition to the loved-up feeling- too much cholinergic action tends to make people feel rigid, robotic, and hyper-cerebral. I am therefore personally skeptical of the benefits of combining something like noopept with MDMA, as the potentiation of some of its qualities may come at the cost of reduced emotional sensitivity. Why trade a feeling of renewed innocence and receptivity with calculating prowess? I doubt this is the best use of a roll.

Anti-tolerance Drugs: This is a category of combinations with tremendous potential to relieve suffering, to the extent that I think of it as a humanitarian tragedy that there are no concerted research efforts currently in this direction. Sufferers of chronic pain and treatment-resistance depression could make use of drugs that help them keep the tolerance to the drugs they depend upon for having a livable life under control. I know this has a lot of the ring of turtles all the way down (“when are you going to get the anti-tolerance drugs for anti-tolerance drugs? And then the anti-tolerance for anti-tolerance for…”) but I am sincere when I say that looking here may pay off in spades. Already we see ibogaine doing other-worldly magnificent things to cure addiction and reverse tolerance. Who knows what a large targeted research program with this focus may discover. Some examples of anti-tolerance drugs include proglumide, ibogaine, and black seed oil for opioids, and flumazenil for benzodiazepines.

Prevent Physical Side Effects: Epidemiological data suggests that chronic or heavy use of 5HT2B agonists may lead to heart valve disease (cf. Fen-Phen), which does not bode well for the long-term (as opposed to acute) safety of many psychedelic compounds. Now, neuroscientist Thomas Ray believes that 5HT2B may be necessary for some of the characteristic psychedelic action of entheogens, so blocking it altogether may come at the cost of eliminating the reason why the drug is interesting. That said, we do know that 5-MeO-DMT is profoundly psychedelic and yet has negligible 5HT2B activity. It would be very useful to know what happens when one combines psychedelics with heavy 5HT2B affinity, like 2C-B and DOB, with 5HT2B antagonists (usually prescription medicines). Would blocking 5HT2B agonism avoid cardiotoxicity? And what would the drug feel like then? Another interesting lead is the affinity of compounds like 2C-E and 2C-T-2 to the 5HT3 receptor, which is predominantly in the gut and modulates feelings like nausea. Additionally, since 5HT3 antagonists are antiemetic it really stands to reason that taking one before e.g. tripping on shrooms may give you a much less, ahem, visceral experience. Finally, I would like to explore the implications of the fact that of all of the compounds in Ray’s study the only one with significant affinity for calcium channels is MDMA. Would this be related to its neurotoxicity? And would taking a calcium channel blocker prevent it? It might still be wise regardless simply as a way to lessen the cardiac load of the compound.

Nootropic Stacks (cf. the Qualia Pill):  Many people who explore nootropics make “stacks”. That is, rather than taking only piracetam, they might take a combination of piracetam, aniracetam, pramiracetam, coluracetam, and l-tyrosine. I suspect that this is popular because most nootropics are pretty mild and often hard to notice, and people want to be able to feel the effects. I generally do not think this is sensible, though, as we don’t understand these substances well enough. More so, branded “nootropic stacks” can have upwards of 30 different psychoactive substances crammed together in half a dozen pills you are supposed to take daily. While I do think there are likely gems to be found in the vast combinatorial space of cognition-boosting chemicals, I simply do not see any way in which the current major brands of nootropic stacks could have done the type of research needed to find them. I therefore do not personally recommend you go out and try such combos, at least not until we know a lot more about how to do combinations properly. If you want to try nootropic stacks, I’d recommend you start with small doses of two or three well-researched nootropics at most and do your own research thoroughly before settling on a particular combination.

NO-MISMATCH-PATTERN

LSD + DMT Visual Replication

Psychedelics and Psychedelics: A classic psychedelic combo that I’ve heard a lot about is LSD + DMT. The state that emerges from this combination is apparently unique, though if you take enough DMT the LSD fades into the background. Apparently psychedelics tend to have a characteristic spectral effect on your brain’s harmonics (see: Connectome-Specific Harmonic Waves on LSD), which manifests in the form of experiencing “vibes of different frequencies” specific to the drug you are taking. The case of LSD and DMT is very interesting, since their characteristic frequencies are sufficiently far apart (to put a number on it, LSD may be in the vicinity of 18Hz while DMT may be close to 30Hz) that they can be separated easily. You thus get a spectral effect of two peaks interfering with one another, oftentimes creating a powerful 3D grid of Moiré patterns, like a super-charged version of the “regular” DMT Chrysanthemum. As a method for spectral analysis, studying the beat patterns of psychedelic drug combos could go a long way in formulating a systematic characterization of their phenomenology. Speculatively, this may even allow us to come up with specific psychedelic drug cocktails that produce maximally consonant harmonious effects.

Idiosyncratic Responses

A final thought to add to this section concerns the fact that people respond differently to drugs. One can reason that if drug A affects 20% of people in a different way while drug B affects 10% of people in a different way, that A + B would lead to 4 different kinds of responses. More so, the more drugs you pile on top of each other, the more specific and individualized the response would be. I think that this is likely true in the general case, but I would argue that it is not universally true. A useful analogy here is with the way people respond to the scent of different molecules: you may lack the gene that encodes the receptor for a particular molecule, but perfumes usually have 30 or more scent-contributing molecules, so the experience of a perfume may be more similar between people than their experience of individual molecules. At the extreme, we have the phenomenon of “white noise scent” where once you mix 40+ molecules in equal (intensity-adjusted) proportions that span scent-space, it all starts smelling the same. The notion of “scent entropy” can be imported to drugs as well: I would expect a kind of inverted U-curve for “how idiosyncratic” the responses to drug combinations are as a function of the total entropy of the combo.

Drug Cocktails From First Principles

The way we aim to understand psychoactive substances at the Qualia Research Institute is in terms of the way they modify the neuroacoustic profile of the brain. And while this is what I see as the most promising approach moving forward, I believe that there is nonetheless a lot of low-hanging fruit at the receptor level of analysis.

The first time I’d thought of trying to emulate the effects of a drug using a cocktail of other drugs came up years ago when I found out that MDMA is likely neurotoxic. At the time I thought perhaps it was just a matter of getting the right dopaminergic, serotonergic, and oxytocinergic activity going for you to replicate the MDMA high. It’s a good thought, and some people have taken it to heart, such as the creators of “Poly”, an MDMA-like cocktail (cf. Kisspeptine). But as we’ll see, MDMA is more complex than that, and we may need to consider far more variables to make a “credible MDMA substitute”.

Looking beyond drug combos of only two or three drugs, and with a nod to concepts from the field of high-entropy alloys (HEAs), we could start thinking about the secret gems to be found in the vast combinatorial space of “high-entropy drug combos”. But what kind of principles could we use to safely combine 5+ drugs? The full story will probably be much, much more complicated than the following approach, but it is still nonetheless worth exploring as a first pass. Namely, to break down each drug in terms of their receptor affinity profile and then use those affinities additively to create arbitrary “synthetic” receptor affinity profiles. There are many reasons why this might not work: receptor affinity may not work linearly or have a clear rule-based behavior. For instance, it is still unclear if a single drug that has affinity for key serotonin receptors (say 5HT2A, 5HT2B, and 5HT7) in addition to working as an NMDR antagonist would produce the same feeling of “synergistic action” as there is between psychedelics and dissociatives. More so, there could be additional intra-cellular signaling specific to each molecule, so that two molecules that work as agonists with the exact same 5HT2B affinity may have different downstream effects inside the neuron, and then those intracellular effects might have phenomenological properties of their own. But leaving all of those caveats and unknowns aside for a moment, what would it look like to create drug cocktails with this method?

ESSFz-mWAAc1Wna

True for both people and drugs!

After giving it some thought I realized that the problem can be reduced to a non-negative least squares (NNLS) optimization (non-negative because, as they say: “you can always take more drugs, but you cannot take less drugs”). It turns out there are already open source implementations of algorithms that solve this optimization problem (for both R and Python)*. So I downloaded the data from the famous Thomas Ray study of psychedelic receptor affinity and played with the data and the non-negative least squares method in a Jupyter notebook for a bit. The first thing I tried was to create a compound like 2C-B but better. Under dubious- but not entirely random- assumptions, I set the desired receptor affinity to be that of 2C-B but with the following modifications: to have the 5HT2B affinity be as low as possible in order to minimize cardiotoxicity concerns, and borrow from MDMA’s unique profile the hypothesis that the Imidazoline receptor is related to heart-opening effects. Additionally, I modified the receptor profile so that the drug would give you more focus than 2C-B by having a higher affinity for the dopamine receptors. To top it off, I racked up the desired receptor affinity for 5HT7, as it has been implicated in providing the more utterly mind-blowing power of psychedelics. I entered these modifications into the NNLS optimizer and the output I got was**:

0.48*2C-B + 0.337*5-MeO-DMT + 0.116*MDMA + 0.043*cis-2a + 0.016*6-F-DMT + 0.005*Mescaline

I see, so since 2C-B is still the backbone of the desired affinity pattern, it appears in high proportion in the mixture as a kind of “base” on top of which the modifications are made. It makes sense that 5-MeO-DMT would come next as it is pretty selective for 5HT7 (remember, the most literally mind-blowing chemical), and MDMA would follow due to the desire for Imidazoline affinity. That by the way, is also probably partly why the formula contains a pinch of Mescaline, to round up that Imidazoline for good measure. I then decided to relax the 5HT7 requirement and instead increase the 5HT6 and 5HT5A, and got the following formula:

0.038*Lisuride + 0.273*2C-B + 0.056*DMT +0.079*Mescaline + 0.15*MDMA + 0.377*RR-2b + 0.018*Ibogaine

And this now looks pretty different. After playing like this for a while, it occurred to me to use this technique to basically try to reconstruct a drug using a non-negative linear combination of the remaining drugs available. Imagine for example that you are stuck in quarantine at your house and you don’t have any 2C-B to kill time (I know! Very relatable isn’t it?), but you do somehow happen to have an assortment of hundreds of other unscheduled random research chemicals. Could you combine them in such a way that you approximate the effects of 2C-B? Well, let’s see.

Here are the “drug reconstructions” the method derives (again, please, don’t try this at home):

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I am pleasantly surprised to see the formulas actually do seem pretty intuitive to me. Take for example the DIPT reconstruction. The top two ingredients are 5-MeO-DIPT and DPT, which are the two closest structural analogues of DIPT in the dataset. Or take the one for DOB: this is the amphetamine version of 2C-B, so it makes sense that both an amphetamine psychedelic (Aleph-2) and 2C-B would make up the top two ingredients. Or consider 5-MeO-DMT, with its most prominent ingredient being 5-MeO-TMT, which is one carbon atom away in terms of structure. Or see how Mescaline’s heart-opening effects are well represented by its reconstruction with MDMA and MDA, while TMA contributes the receptor affinity characteristic of the trimethoxy class of functional groups, along with another Mescaline-like phenethylamine, 4C-T-2. Alas, here is where an imperfect understanding of drug interactions could come and bite us in the ass: if 4C-T-2 is anything like 2C-T-2, it might have some MAOI action, which could be potentially very dangerous to combine with compounds like MDMA. Needless to say, before you go out and try these crazy drug cocktails, we first need a thorough understanding of each drug well beyond just its affinity to “only” 30 or so receptors.

Now, not every reconstruction makes sense to me, and really only a few substances have what I would call a descent mean squared error. See the receptor affinity tables below for examples of both successful and unsuccessful reconstructions (only non-zero entries shown):

DOB and 2C-T-2 have some of the lowest errors in the sample, meaning that their reconstructions are pretty good, while Ibogaine and MDMA have two of the worst error rates, and their reconstructions are still obviously pretty far from the goal. Naturally, if we were ever to test this method in the lab (with e.g. a drug discrimination paradigm) we would probably start with the most accurate reconstructions first. For instance, train rats to distinguish between 2C-B and DOB, and see if administering the (2C-B-containing) “DOB reconstruction” makes the rats think they got DOB rather than 2C-B.

Master Druggist (Synapse? Dendrite?)

I would like to conclude this essay with an interesting speculation: what if we developed drug combos like we develop perfumes? It is my appreciation that it takes a very high level of intelligence, domain expertise, and psychological robustness to be able to contribute usefully to the field of psychonautics. Sasha Shulgin spent over 30 years taking hundreds of completely new drugs, and I would very much trust his judgement about what makes a great psychedelic drug combo than I would trust a random BlueLight or Erowid user. (As an aside: Shulgin was extremely cautious in his approach, but he certainly wasn’t doing some of the low-hanging fruit on safety, such as wearing a heart monitor or measuring his blood pressure when taking a new drug, for starters. Future systematic psychonautic work should also record as much biometric data as is feasible). You wouldn’t put on a perfume made by someone who has only ever worn Axe, would you? Training a “Nose” takes up to 7 years, and it involves becoming deeply familiar with the scent of a long list of molecules, accords, and perfumes. Likewise, I’d expect that in order to be qualified to find extremely good drug combinations, one would first need to become familiar with the effect of many different individual drugs, “natural drug accords” (e.g. peyote), and designed drug cocktails. Only once you have an intuitive sense of how e.g. the sigma receptor interacts with the 5HT1A receptor would I trust your judgement about adding a pinch of agmatine to your already convoluted mixture of 20 psychoactive substances. A Super-Shulgin Academy could train people to be professional drug cocktail makers (if perfumers are called “Noses” would we call Super-Shulgin certified cocktail makers “Dendrites”?). As discussed above, this assumes that we can do this safely, which I suspect will be possible once we map out the space of dangerous combinations and receptors we shouldn’t mess with to avoid side effects like cardiotoxicity (e.g. 5HT2B, 5HT3A, calcium channels, etc.).

You come to the master cocktail designer with a general concept for a new recreational drug, and they would come up with activity profiles that best evoke those feelings. The Dendrite would select from hundreds or thousands*** of pure chemicals and accords to create your unique cocktail. As is the case with Noses in the perfume industry, a Dendrite would tend to have a set of about one to two hundred “frequently used” compounds, and a dozen or so “signature” ones they’re deeply familiar with and that usually reveal who the Druggist is, if found in large proportions in the end product. Of course there would be “house favorites” (e.g. the classic “ambroxan bomb” of Dior fragrances for men) and chemical fads (e.g. the wide adoption of Iso E Super in 90s perfumes). Every year would come with a new season of amazing, safe, and uniquely interesting recreational drug cocktails.

In perfumery you find both natural and synthetic “accords”: “Violet reconstructions” attempt to emulate the smell of violet but in a much more long-lasting, storable, and versatile way. Good Dendrites would not only use “natural accords” such as “peyote” or “marijuana plant” but would also make their own, aided with computer models and datasets of trip reports along with their own first person experiences. In both perfumery and professional drug cocktail making we would study accords packed with combos of qualia-triggering chemicals, and a Dendrite could be known not only for making good final products, but for making excellent accords with predictable and desirable effects.

To finalize the analogy (and this article) we could also discuss the way in which perfumes feel “broad spectrum” thanks to being constructed by combining “top, heart, and base notes”. Roughly speaking, top notes tend to “feel higher frequency” (such as citric scents) while base notes tend to “feel low frequency” (such as woody scents), not unlike how a symphony will tend to combine sounds across the spectrum. The most interesting, voluptuous, and commercially viable combos would also probably have a broad spectrum of activity. They would be anxiolytic, exciting, relaxing, trippy, and empathogenic to various degrees all at once. They would combine fast, slow, and spiritual euphoria in a single power punch of qualia cornucopia. As such, each drug cocktail made this way would entail an entire worldview – a whole realm currently hidden in the vast state-space of consciousness.



* For an intuition: recall from linear algebra that a basis of n linearly independent vectors span an n-dimensional vector space. When the vector that you are trying to reconstruct is not in the span of your basis, the best you can do is to project your vector to the nearest hyperplane of the spanning space. Adding the constraint that you can only make non-negative linear combinations with your basis vectors, you find that the span will look like an ‘inverted pyramid’, and the least-squares solution will be the point of that inverted pyramid that is closest to your desired vector. This is why most of the reconstructions only use a subset of the available drugs in the dataset. In most cases, the desired vector (i.e. affinity profile in this case) will be outside of the inverted pyramid of the non-negative span, and the closest hyperplane will be a linear combination of only a subset of the building blocks- those which span that particular hyperplane. I.e. the solution is the projection to the nearest hyperplane segment covering the non-negative span. This is what the NNLS method is doing under the hood.

** Note: It’s important to point out that these are not dosages. The coefficients provided by the non-negative least squares method apply to the normalized affinity “npKi“, which is the receptor affinity normalized by the highest affinity among the receptors. The coefficients will be correlated with “proportion of a standard active dose” but there will be an error caused by the pretty tricky confounder that molecules vary in their “breadth of affinity”. Additionally: the psychoactivity of each receptor is not the same, we are not considering saturation effects, the difference between partial and full agonists is not taken into account, downstream effects are ignored, etc. etc. Needless to say, there is still quite some work to be done to transform these coefficients into meaningful dosages.

*** List of Psychoactive Drugs a professional Dendrite would be expected to be familiar with:

L-Tyrosine, L-DOPA, Apomorphine, Flumazenil, CPZ, BPAP, PPAP, Cabergoline, DAR-0100, Lisuride, Pergolide, Pramipexole, Rotigotine, Biopterin, PLP, Aminepetine, PCP, Marijuana, Dextromethorphan, Isoflavones, Citicoline, Metadoxine, Arecoline, Niacinamide, Paraxanthine, a-GPC, Acetylcarnitine, AR-R17779, GTS-21, Ispronidine, PHA-543,613, SSR-180,711, WAY-317,538, Hopantenic Acid, IDRA-21, Propentofylline, PRL-8-53, Trytophan, Picamilon, Betahistine, A-349,821, Cipoxifan, Creatine, Mildronate, Pregnenolone, Nisoxetine, Orexin, CP-39,332, Esreboxetine, Daledalin, AM-1248, Phenoxybenzamine, Symbescaline, Phentolamine, Isomescaline, Tolazoline, a-Methylfentanyl, Ketamine, Dichlorpane, 3-meo-pcp, Hex-en, Paraflourofentanyl, 3-Methylfentanyl, Metofoline, Buscaline, O-DT, Nortilidine, Thiobuscaline, Dizocilpine, Rolicyclidine, Phenescaline, Tenocyclidine, Methoxyketamine, pFPP, 5-me-MDA, 4-MAR, 1,4-Butanediol, 2-Methyl-2-Butynol, GHV, GVL, Mebroqualone, Benzylbutylbarbituates, Phenmetrazine, 3-Fluorophenmetrazine, Crack, Cocaine, Coca, Kava, Phenylacetylindoles, Benzoylindoles, Napthoylindoles, Adamantoyindoles, Pineapple Sage, Kokum, Brahmi, Artic Weed, Skullcap, Salvia Splendens, Coriander, Rhodiola Rosea, Velvet Bean, Bitter Orange, St. John’s Worth, Grape Seed Extract, Tulsi, Blessed Thistle, 3-Desoxy-MDA, Skatole, Isoindole, Indole, Benztropine, Diphenhydramine, Niaprazin, Doxylamine, Alaproclate, Zopiclone, Ifoxetine, Methylmethaqualone, Panuramine, Meta-Tyramine, Para-Tyramine, 2M2B, Pirandamine, SB-649,915, Epinephrine, Mepyramine, Octopamin, Delucemine, Oxidopamine, β-Methylphenethylamine, Mesembrine, Psuedoephedrine, Etolorex, Cathine, Cathinone, Ethcathinone, Norfenfluramine, Fenfluramine, Phentermine, Metaescaline, n-Ethylbuphedrone, Naphyrone, Pyrovalerone, Isopropylamphertamine, Clobenzorex, Pholedrine, Chlorphentermine, Xylopropamine, DON, DOPR, TMA, Methyl-BOB, Tetramethoxyamphetamine, 4-MTA, Bromatane, Hydroxyzine, BNC-210, CL-218,872, L-838,417, SL-651,498, S32212, 6-CAT, TAP, ETAI, IMP, Lorxaserin, Cisapride, Tegaserod, AS-19, E-55888, LP-12, LP-44, LP-211, Etoperidone, Lorpiprazole, Lubazodone, Mepiperazole, 5-TASB, TB, 3-TE, 4-TE, 2-TIM, 3-TIM, 4-TIM, 3-TM, 4-TM, TMA, TMA-2, TMA-3, TMA-4, TMA-5, TMA-6, 3-TME, 4-TME, 5-TME, 2T-MMDA-3a, 4T-MMDA-2, TMPEA, 2-TOET, 5-TOET, 2-TOM, 5-TOM, TOMSO, TP, TRIS, 3-TSB, 4-TSB, 3-T-TRIS, 4-T-TRIS, 44-BMAR, 3-MOMC, Prolintane, SDB-001, AB-FUBINACA, Dichloromethylphenidate, AB-PINACA, MN-24, 5F-MN25, A-836,339, ADBICA, 5F-NNEI, RCS-4, RCS-8, MPHP, 6-APDB, 4-HMP, EDMA, a-PBP, Methylhexamine, a-PPP, 4-FMD, EIDA, Phenylphrine, UWA-101, MPBP, RH-34, F-2, F-22, MR-2096, Adrenochrome, AET, Carbogen, DOB, DOM, Desmorphine, Ethylcathinone, Ehylene, GHV, Hypocretin, mCPP, MDPR, Methaqualone, TFMPP, CPP, MeoPP, A2, Salvinorin A, Scoplamine, TMA-2, BDO, 2c-B-FLY, 4-Flouromethcathinone, 4-HO-MPT, U4EA, 4-MTA, Phenylpiracetam, Aniracetam, Coluracetam, Pramiracetam, Melatonin, NRG-3, Theobromine, A834-735, Oxytocin, NZT-48, Heroine, 3-HO-PCP, MAOIs, 4-MeO-PCP, 3c-P, 5-IAI, Atropine, 5-IT, Bufotenin, 5-MAPB, 4-Aco-MiPT, 6-MAPB, ALD-52, AMMI, MET, D2PM, DET, CBD, CBN, LY-2183240, SF-SDB-005, AM-404, EG-018, DXM, FDU-PB22, AL-LAD, 3-MeOMC, 2-MeO-Diphenidine, 4-MPD, bk-MDMA, 4-MeO-a-PVP, GHB, 4-MeO-PBP, MBDB, 4-MeO-PV9, Fentanyl, 4F-PV8, a-PBT, BDB, a-PVT, 2-FMA, Dibutylone, 5-Meo-DiPT, Diclofensine, Methcathinone, DL-4662, MDEA, MDPPP, Methylone, Butylone, NEB, Phenibut, PV-8, GABA, 25B-NBF, Etaqualone, 5-API, Ethylone, Pentadrone, 4F-PVP, 25C-NBF, BZ-6378, C30-NBOMe, RH-34, MDAT, MDMA, MDMAI, Dimethocaine, Synthacaine, 3β-FBT, 5-MeO-BFE, 3,4-DMMC, AM-1248, MTTA, AM-2233, URB-597, AM-694, AM-087, BAY-38-7271, AB-005, A-796260, URB-754, 2-DPMP, a-PVP, 25N-NBOMe, 5-MeO-NiPT, Dexmethylphenidate, Buphedrone, RTI-111, Pentylone, 25I-NBF, Flourotropacocaine, Flourococaine, Cocaethylene, 25D-NBOMe, 25E-NBOMe, DMT, 5-Meo-DMT, 2C-I, 2C-E, 25I-NBOMe, 25I-NBOH, 25C-NBOMe, MXE, MDA, MDE, Mescaline, Ibogaine, Bromo-DragonFLY, Salvinorum, RU-28306, 2NE1, Psilocybin, HOT-7, JWH-018, JWH-250, 5-Meo-EiPT, AM-2201, 5-APDI, BZP, BZ, 4-MEC, MDPV, Bakers Ammonia, THC, THCv, Chloral, Chlorabutynol, MT-45, 5-Methyl-Ethylone, Methylphenidate, Ethylphenidate, 6-APB, 5-APB, Muscimol, 5-MeO-MALT, AKB48, 3,4-CTMP, PB-22, Diphenidine, UR-144, Flubromazepam, HU-210, MPA, XLR-11, MN-18, Naltrexone, STS-135, Gabapentin, 5-MAPB, Nitrous, Etizolam, Mephedrone, Pyrazolam, Methedrone, AH-7921, Phenazepam, AMT, OxyNEO, DPT, 5-MeO-AET, 4-Aco-DMT, EAM-2201, 5-MeO-DALT, 5-MeO-AMT, Acefentanyl, Ehylphenidate, 4-HO-MiPT, THJ-2201, 5-APDB, 5-EAPB, 4-HO-DPT, DOC, bk-2c-B, Escaline, THJ-018, 4-HO-MET, 2-AI, 2-MeO-Ketamine, Methoxphenidine, Ketamine, 2c-EF, Methamphetamine, Dextroamphetamine, Nitracaine, DALT, IAP, 4-fa, 2-Me-DMT, 4-fcocaine, Isopropyl Nitrate, 5-MeO-TMT, Piracetam, Amatadine, Choline, Memantine, 5-HTP, Camfetamine, Methallyescaline, LSZ, LSA, NBOMe-Mescaline, Loperamide, LSB, 25P-NBOMe, 25G-NBOMe, 3-MeO-PCE, MAM-2201, PCP, MPTP, MDAI, DOI, BB-22, EA-3167, BDF, L-Theanine, Dimethylone, Hydrocodone, Codeine, Morphine, Dilaudid, Oxycontin, Alpralozam, Diazepam, Fentanyl, Soma, Suboxone, Marinol, Seroquell, Trazodone, Lithium Bicarbonate, Abilify, Methadone, Amitriptyline, Strattera, Chloral Hydrate, Bromazepam, Buperonorphrine, Bupropion, Chlordiazepoxide, Clonidine,Clonazepam, Cyclobenzaprine, Dramamine, Benadryl, Ethchlorvynol, Fluoxetine, Tianeptine, Amineptine, Flurazepam, Metaxalone, Mirtazapine, Nalaxone, Nimetazepam, Oxymorphone, Paroxetine, Zopidone, Pregabalin, Promethazine, Risperadone, Selegiline, Sertraline, Sumatripan, Tiagabine, Propofol, Propanolol, Tiletamine, Zolpidem, Lotus, Aloe, Datura, Calendula, Chacruna, Galangal, Chaliponga, Chamomile, Damiana, Fever Few, Nightshade, Ginseng, Foxglove, Lavender, Henbane, Mugwort, Hemlock, Monkshood, Dream Herb, Capsaicin, Amanita, Hawaiian Baby Woodrose, Ergot, Hops, Imphepho, Indian Warrior, Kanna, Dagga, Kratom, Mandrake, Valerian, Nicotiana Tobacum, Nicotiana Rustica, Mimosa Hostilis, Morning Glory, Nutmeg, Opium Lettuce, Poppy, Sinicuichi, Syrian Rue, Tree Tobacco, Wormwood, Yohimbe, Yopo, Khat, Peyote, Cannabis, Catnip, Phalaris, San Pedro, Soma (ancient), Chacruna, Acacia, Ephedra, Mulungu, Mullet Fish, Siganus Spinus, Fugu, Sting-ray Venom, Bufo Alvarius, Epipedobates Tricolor, Waxy Monkey Frog, Salamandra Salamandra, Cobra & Scorpion Venom, Reindeer Urine, Glomeris Marginata, Sergeant Major, Grouper, Bluefish, Brass Beam, Flathead Mullet, Golden Goatfish, Rabbit Fish, Goat Fish, Adrafinil, DHEA, Dilantin, DMAE, Fipexide, Gerovital, Ginko, Black seed oil, HGH, Hydeigine, Meclofenoxate, Modafinil, Oxiracetam, Phenyton, Vasopressin, Vinopocetine, Bee Venom, Monkey Frog, UCM-707, AM-1172, VDM-11, VDM-13, OMDM1, OMDM2, LY-2318912, O-2093, OL-135, URB-597, URB-532, AEM, AL, ALEPH, ALEPH-2, ALEPH-4, ALEPH-6, ALEPH-7, ARIANDE, ASB, B, BEATRICE, BIS-TOM, BOB, BOH, BOHD, BOM, 4-Br-3,5-DMA, 3-Br-4,5-MDA, 2C-B, 3C-BZ, 2C-C, 2C-D, 3C-E, 2C-F, 2C-G, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-N, 2C-H, 2C-N, 2C-O-4, 2C-P, CPM, 2C-SE, 2C-T, 2C-T-4, 2C-T-2, 2C-T-7, Ψ-2C-T-4, 2C-T-8, 2C-T-9, 2C-T-13, 2C-T-15, 2C-T-17, 2C-T-21, 4-D, β-D, DESOXY, 2,4-DMA, 2,5-DMA, 3,4-DMA, DMCPA, DMMDA, DMMDA-2, DMPEA, DOAM, DOBU, DOEF, DOET, Ψ-DOM, DON, DOPR, E, EEE, EEM, EME, EMM, ETHYL-J, ETHYL-K, FLEA, G-3, G-4, G-5, GANESHA, G-N, HOT-2, HOT-17, IDNNA, IM, IP, IRIS, J, LOPHOPHINE, M, 4-MA, MADAM-6, MAL, MDAL, MDBU, MDBZ, MDCPM, MDDM, MDHOET, MDIP, MDMC, MDMEO, MDMEOET, MDMP, MDOH, MDPEA, MDPH, MDPL, MDPR, ME, MEDA, MEE, MEM, MEPEA, META-DOB, META-DOT, METHYL-DMA, METHYL-DOB, METHYL-J, METHYL-K, METHYL-MA, METHYL-MMDA-2, MMDA, MMDA-2, MMDA-3a, MMDA-3b, MP, MME, MPM, ORTHO-DOT, P, PE, PEA, PROPYNYL, SB, TA, 3-TASB, 4-TASB, Tropane, Vomeronasal Organ, Tropine, Hyosyamin, Dihydrokavain, Hyoscine, Myrcene, Ecgonine, 7-OH-DPAT, Benzoylecgonine, Sunifiram, Hydroxytropacocaine, Estrogen, Methylegonine Cinnamate, Estradiol, Catuabines, Estratetraenol, Phenyltropane, Androstenone, Civetone, Adrostenol, 5F-PB-22, Androstadienone, CBG, THCa, CBC, CBDa, Anandamide, 2-AG, CBL, CBDv, CBCv, CBGv, CBGm, Ibogaine, Noribogaine, Tabernanthine, Coronaridine, Ibogamine, Vaocangine, 18-MC, 5-MeO-Alkyltryptamine, β-Carboline, Tryptoline, Pinoline, Harmane, Harmaline, Harmine, Harmalol, Harmalan, Harmanamide, Acetylnorhormine, Bufotenin Oxide, DMT-N-Oxide, 5-MeO-Tryptamine, 5-OH-DMT, 5-MeO-DMT-Oxide, 3,4-Dimethoxyphenylamine, 6-MeO-Harman, Anethole, Safrole, Estragole, Monolignol, Pukateine, Glaucine, THP, Nantenine, Thujone, Lagochilin, Nicotine, Carbachol, Methacholine, ME-18-MC, 18-MAC, Tryptamine, β-Methyl-Phenethylamine, NMT, Voacanga Africana, Vachellia Farnesiana, Duboisia Hopwood, Acacia Victoriae, Anadenanthera Penegrina, Phalaris Aquatica, Echinopsis Lageniformus, Cylindropuntia Echinocarpa, Leptactina Densiflora, Fennel, Justica Pectoralis, Lactucarium, Glacium Flavum, Zornia Latifolia, Argemone Mexicana, Silene Undulata, Catharanthus Roseus, Desfontainia, Heimia Salicifolia, Lophophora, Sea Urchin Eggs, Bethanechol, Muscarine, Pilocarpine, Oxotremorine, Aporphine, Leonurine, Bungacotoxin, Tetrodotoxin, Taurine, Opiod Peptide, Streamlined Spinefoot, Blue-Spotted Spinefoot, Dusky Spinefoot, Marbled Spinefoot, Little Spinefoot, Salema, Phyllomedusa, Blue Sea Chub, Brow Chub, Conuict Surgeonfish, Yellowstipe Goatfish, Finstripe Goatfish, Acute Jawed Mullet, Coral Grouper, Platypus Venom, Slow Ioris Venom, Pygmy Slow Ioris Venom, Giant Leaf Frog, Gluten Exorphin, Soymorphin-5, Dermophin, 7-PET, Dimethyliambutene, Proopiomelanocortin, β-Endorphine, Dynorphin, Adrenorphin, Salvinorin B Methoxymethyl ether, Amindophin, Enkephalins, Salvinorin B ethoxymethyl ether, Opiorphin, Herkinorin, RB-101, DPI-221, Spinorphin, Kelatorphan, Delta-Pheylalanine, Thiorphan, Tynorphin, Hemorphon-4, Valorphin, Casomorphin, Gliadorphin, Rubiscolin, Deltorphin, MG6, MT-45, Myrophine, Acetorphine, Acetylmorphone, Actiq, Benzethidine, BU-48, BRL-52537, Pethidine, Naloxol, Betacetylmethadol, Methorphan, Bezitramide, RAM-378, Bromadol, Eriadoline, BW373U86, Thebaine, C-8813, Menthol, 8-CAC, Capperidine, Matrine, Chloromorphide, a-Chlorocodide, HZ-2, Codeinone, LPK-26, Codoxime, AD-1211, Conorfone, DADLE, Butorphanol, DAMGO, Semorphone, Dextromoramide, Sutentanil, Diampromide, Zenazocine, Difenoxin, Thebacon, Dihydroetorphine, Tilidene, Dimenoxadol, Xorphanol, Dipipanone, Dipropanoylmorphine, Doxpicomine, DPI-3290, Drotebanol, Endomorphin, Eseroline, Ethoheptacine, 14-Ethoxymetopon, Ethylmorphine, Etorphine, Etoxerdine, Furethidine, Heterocodeine, RAM-320, IBNtxA, IC-26, 1-Iodomorphine, Isomethadone, Ketobemidone, Ketorfanol, Lefetamine, Levorphanol, Loperamide, Meprodine, Metofoline, Metopon, Morpheridine, Morphine-N-Oxide, Morphinone, MR-2096, Nicocodeine, Nicomorphine, Normethadone, Ocefentanyl, Ohmefentanyl, Oxpheneridine, Oxymorphazone, Oxymorphol, Oxymorphone, Pentamorphone, PEPAP, Pericine, Phenadoxone, Phenempromide, Phenazocine, Pheneridrine, Phenomorphan, Picenadol, Piminodine, Piritramide, Proclilidine, Prodine, Proheptazine, Properidine, Prosidol, R-30490, R-4066, Ro4-1539, RWJ-394674, Sameridine, SC-17599, Methyldesorphine, Hydroxypethidine, 4-Fluouropethidine, Cannabis Indica, Cannabis Sativa, Cubensis, Hash, BHO, Delta-9-THC, 25TFM-NBOMe, 2C-B-BZP, 2CBFLY-NBOMe, 2CD-5Et0, 5-I-R91150, A-372,159, 2-Bromo-LSD, a-5IA, PWZ-029, L-655,708, TB-21007, 5-Ethoxy-DMT, 5-Ethyl-DMT, 7,N,N-TMT, VER-3323, YM-348, Alnespirone, 8-OH-DPAT, Aminorex, Batoprazine, 5-BT, BIMU-8, BMY-14802, BRL-54443, BW-723C86, 5-CT, CGS-12066A, Cinitapride, CJ-033,466, CP-135,807, CP-809,101, CP-93,129, CP-94,253, N,a,-DEPEA, Dimemebfe, RA-7, E-6801, E-6837, Eltoprazine, Methylsulfonylmethane, EMD-386,088, EMDT, ST-1936, Fluprazine, Indorenate, Jimscaline, L-694,247, Lasmiditan, APD-356, MMDPEA, LY-293,284, LY-310,762, LSD-pip, LPD-824, LSM-775, 5-MT, MBZP, Methyl-MMDA-2, a-MS, MK-212, Mosapride, Org 12,962, Org 37,684, Quipazine, 6-Nitroquipazine, NBUMP, 1-NP, 5-(Nonyloxy)Tryptamine, PHA-57378, PNU-181731, PNU-22394, Propylhexedrine, Prucalopride, PRX-03140, Psilocin, RDS-127, RH-34, Ro60-0175, Ro60-0213, RS-56812, RS-67,333, RU-24,969, RU-28306, SKF-97,541, SR-57227, Tandospirone, Tegaserod, TFMFly, pTMFPP, U-92,016A, SCA-136, TD-5108, Vortionetine, WAY-161503, WAY-208,466, WAY-629, Xaliproden, YM-31636, Zacopride, A-423,579, A-84,543, Abercarnil, 5-Br-DMT, Sugar, Acetildenafil AMMI 4C-D, AS-8112, Astemizole, Asymbescaline, Azapride, BAY-38-7271, BAY-59-3074, BAY-60-6583, Benproperine, Benzylmorphine, Berberine, 2-Pyrrolidone, JBIR-03(1), 1′-O-Acetylpaxilline, Penijanthine A, Emindole DA (1), Petromindole, Emindole SA (2), JWH-133, Napthylmethylindoles, Napthyolpyrroles, Napthylideneindenes, Cyclohexylphenols, Indole-2-Carboxamides, C3 Amino-Indoles, Cymserine, Hodgkinsine, Physostigmine, Psychotridine, Psychotria Colrata, Yuremamine, Gevotroline, Latrepirdine, BMY-7,378, Boldine, BP-897, Brexpiprazole, 4-Bromo-3,5-Dimethoxyamphetamine, Bromopride, Caroverine, CGS-20625, Cinchocaine, DAA-1097, DAA-1106, DOTFM, DMPEA, DMCM, Dyclonine, Ethylvanilin, Evoxine, Furoquinoline Alkaloids, Gabazine, GBLD-345, Rapacuronium, Mivacurium Chloride, Cisatracurium Besilate, DTC, Cloroqualone, Diproqualone, Mecloqualone, Methylmethaqualone, Eszopiclone, TP-003, TP-13, TPA-023, Y-23684, Pagoclone, Pazinaclone, Suproclone, Suriclone, Zapiclone, CGS-9896, NS-2664, NS-2710, Pipequaline, RWJ-51204, SB-205,384, ELB-139, Acamprosate, GABOB, N4-Chloroacetylcytosine Arabinoside, (+)-CAMP, CACA, AZD-3355, 1,4-Butanediol, XP19986, Rosarin, Rosavarin, Atagabalin, Gabapentin Enacarbit, Hopantenic Acid, Imagabalin, 4-Methylpregabalin, PD-217,014, Afloqualone, Rocuronium Bromide, Vecuronium Bromide, Pipecuronium Bromide, Pancuronium Bromide, Amyl Nitrate, Atracurium Besilate, BWA444, Benzylisoqualone, Papaverine, Protopine, HS-342, HS-347, HS-310, Emylcamate, Eperisone, Febarbamate, Flavoxate, Inaperisone, Acamprosate, Progabide, Tiagabine, Lanperisone, Mephenesin, HS-692, HS-693, HS-704, HS-705, HS-626, Chlorzoxazone, Cisatracurium Besilate, Curare, Cyclobenzapine, Dantrolene, Decamethonium, Difebarbamate, Dihydrochanclonium, Doxacurium Chloride, Gallamine Triethiodide, Gantacurium Chloride, Hexafluronium Bromide, Meprobamate, Metaxalone, Methocarbamol, Norgesic, Orphenadrine, Pancuronium Bromide, Phenprobamate, Pipecuronium Bromide, Premazepam, Promoxolane, Quazepam, Rocuronium Bromide, Silperisone, Sulazepam, Suxamethonium Chloride, Suxethonium Chloride, Tetrabamate, Tizanidine, Tolperisone, Gigantine, BAY-73-6691, Indiplon, Nitrosoprodenafill, Zaleplon, Udenafil, Sulfoaildenafill, Sildenafil, Ocinaplon, Alpidem, Bamaluzole, DS-1, Fadrozole, Fazadinium Bromide, Imidazopyridine, Minodronic Acid, Bisphosphonate, Miroprofen, Necopidem, AL-LAD, DBT, a.O-DMS, 2,a-DMT, a,N-DMT, ETH-LAD, a-ET, 4-HO-DBT, 4-HO-pyr-T, MBT, 4,5-MDO-DIPT, 5,6-MDO-DIPT, 4,5-MDO-DMT, 5,6-MDO-DMT, 5,6-MDO-MIPT, 5,6-MeO-MIPT, 5-MeO-pyr-T, 5-MeO-NMT, 6-MeO-THH, 5-MeS-DMT, PRO-LAD, pyr-T, a,N,O-TMS, Olprinone, Telcagepant, Febrifugine, Halofuginone, MK-0249, LY-156,735, Ramelteon, Tasimelteon, SL-164, Quinazoline, Albaconazole, Altaserin, ATC-0175, Canertinib, Cediranib, Doxazosin, Fluproquazone, Gefitinib, Katanserin, Lapatinib, Agmatine, Amantadine, AP-7, AP5, Aptiganel, CGP-37849, 7-CTKA, DCKA, DXO, MK-801, SL-82.0715, Esketamine, Ethanol, NEFA, Besonprodil, Gacyclidine, Gavestinel, Huperzine A, Ifenprodil, Indantadol, Metaphit, Memantine, LY-235,959, Lubeluzole, Levomethadone, Kynuretic Acid, Midafotel, Neramexane, Nitromemantine, PEAQX, Perzinfotel, 8A-PHDQ, Remacemide, Rhynchophylline, Sabeluzole, Tiletamine, Tramadol, Xenon, Hydroxchloroquine, Antrafenine, Bedaquiline, GSK-299423, JTC-801, JTE-907, LGD-2226, PBT-2, PF-2545920, SB-215,505, SB-277,011-A, SB-742,457, BHF-177, BHFF, BSPP, Cartazolate, CGP-7930, Clomethiazole, Etazolate, Etomidate, Felbamate, Fospropofol, Gaboxadol, Glutethimide, GS-39783, Ibotenic Acid, ICI-190,622, Isoguracine, Isonipecotic Acid, Loreclezole, Methyprylone, Allopregnanolone, 5a-Dihydroprogesterone, Progesterone, THDOC, Alfadolone, Alfaxalone, Ganaxolone, Hydroxydione, Minaxolone, Org-20599, Pregnane, Piperadone, Propanidid, Propofol, Pyrithyldione, ROD-188, Stiripentol, Thiomuscimol, Thymol, Tybamate, QNB (BZ), Scopolamine, Midazolam, Sodium Pentathol, Amobarbital, Blue 88, Adinazolam, Alphenal, Bentazepam, Bromisoval, Camazepam, Carbromal, Centalun, Chloralodol, Chronobiotic, Cinolazepam, Clorazepate, Cloxazolam, Cyclopyrrolones, Delorazepam, Dichloralphenazone, DPH, Doxefazepam, Doxylamine, Embutramide, Eplivaserin, Ethinamate, Ethyl Ioflazepate, Fludiazipam, Heptabarb, Oleamide, Org 21465, Org 25435, Paraldehyde, Phenobarbital, Propiomazine, Promethazine, Propylbarbital, QH-II-66, Glycine, Quetiapine, SH-053-R-CH3-2’F, Sulfonmethane, Tetrabarbital, Tetronal, Trional, Trytophol, Acaprazine, Acebrochal, Acetylglycinamide Chloral, Almorexant, Detomidine, Bromouriede, Benzoctamine, Barakol, Bekhterev’s Mixture, Fasiplon, Fenadiazole, Fluperlapine, JM-1232, Inebriating Mint, Ro41-3696, Methapyrilene, Minitran, Nisobamate, Oxanamide, Oxomemazine, Panadiplon, Pazinaclone, Pentabamate, Petrichloral, Potassium Bromide, Procymate, Saripidem, Vinybital, Vinbarbital, Valofane, Validolum, Valeric Acid, Unisom, U-90042, U-89843A, Triclofos, 2,2,2-Trichloroethanol, TCS-OX2-29, SX-3228, Suvorexant, Sigmodal, SB-649,868, 6-APA, 77-LH-28-1, Adimolol, Alfentanil, Amedanil, Amedalin, BMS-564,929, Binospirone, Carburazepam, Clazolam, Clobazam, Clobenzepam, Clotiazepam, Thienodiazepine, Brotizolam, CP-14145, Cyclazodone, CSP-2503, Cycloserine, Cytisine, Demoxepam, Chlordizepoxide, Dibenzepin, Dihydroergocorine, Dihydroergocristine, DHEC, Dihydroergotamine, 17-DMAG, Dimiracetam, Doliracetam, Droperidol, Dihydrotestosterone, Dutasteride, Edaravone, EGIS-12,233, Elfazepam, Elzasonan, Enilospirone, Ergoloid, Ergotamine, Ergocrytine, Ergocristine, Ergovaline, Etazepine, Evodiamine, Fenmetramide, Fenozolone, Flunitrazepam, Flutazolam, Flutemazepam, Flutoprazepam, Fosazepam, GW-803,430, Halazepam, Haloxazolam, Herbimycin, Horsfiline, HT-0712, Icilin, Clazepam, Indoprofen, Ipsapirone, Isatin, Ketazolam, KF-26777, Lofendazepam, Lopirazepam, Loprazolam, Lorazepam, Lormetazepam, Menitrazepam, Meclonazepam, Menitrazepam, NMSP, Mexazolam, THCI, THCII, THCIII, THCIV, THCV, Mosapramine, Motrazepam, NBQX, Nevirapine, Nimetazepam, Nitrazepam, Nitrazepate, Nitroxazepine, Nordazepam, Nortetrazepam, Oxazepam, Oxatomide, Paliperidone, Prazepam, Pivoxazepam, Pirquinozol, Pirenzepine, Pinazepam, Pemoline, Paraxazone, Palonosterone, Proflazepam, Propizepine, Razobazam, Revospirone, Ripazepam, Ro15-4513, Ro48-6791, Ro48-8684, Ro5-2904, Ro5-4864, Ro64-6198, Ropinirole, RPL-554, RS-102,221, SL65.0155, Spiroxatrine, Temazepam, Tetrazepam, Thozalinone, Tolufazepam, Triflubazam, Vardenafil, Ziprasidone, Zolazepam, Zomebazam, Zometapine, Pyrazolodiazipines, Triazolodiazipines, Estazolam, Flubromazolam, Triazolam, Nitrobenzodiazepines, Pentazocine, 8-HO-PBZI, A-366,833, ABT-202, Sympathomimethies, ABT-239, ABT-418, Almotriptan, BD-1008, LR-132, BD-1031, Singma Agonists, BD-1018, 4-PPBP, Alazocine, BD-1052, Butinoline, Clemizole, CPHPC, Desoxy-D2PM, Citalopram, Ditolyguanidine, Escitalopram, Fluoxetine, Fluvoxamine, Tgmesine, L-697,384, PRE-084, S33005, SA-4503. Siramesine, Venlafaxine, Clonidine, VUT-8430, UR-AK49, Moroxydine, Altinicline, Anabasine, 3-Bromocytine, Bradanicline, Cotinine, Desformylflustrabromine, Dianicline, DMPP, Epibatidine, Epiboxidine, Lobeline, Myosmine, PNU-120,596, PNU-282,987, ABT-089,Rivanicline, RJR-2429, Phantasmidine, Sazetidine A, SIB-1553A, TC-1698, TC-1827, TC-2216, Tebanicline, 2,3,4,5-Tetrahydro-1,5-Methano-1H-3-Benzazepine, UB-165, Varenicline, FE-β-CPPIT, FB-β-CPPIT, RTI-336, NVP-AUY922, Pleconaril, RTI-177, RTI-371, Calea Ternifolia, African Dream Herb, Ambutonium Bromide, Hyoscamine, Ilex Guayusa, Abediterol, Aclidinium Bromide, Benzilycholine Mustard, Bevonium, Bornaprine, Cyanodothiepin, Darifenacin, Dexetimide, Dicycloverine, Etybenzatropine, Fenpiverinium, Fesoterodine, Homatropine, Hydroxyzine, Imidafenacin, Ipratropium Bromide, Methylatropine, Methylhomatropine, Octatropine Methylbromide, PD-0298029, PD-102,807, Pipenzolate, Piperidolate, Tiotropium Bromide, Anisodine, Benacytazine, Butylscopolamine, CAR-226,086, CAR-301,060, CAR-301,196, Caramiphen, Clidinium Bromide, Ditran, EA-3167, EA-3443, EA-3580, EA-3834, JB-318, JB-336, Methylscoplamin Bromide, Oxapium Iodide, Oxitropium Bromide, Polyfothine, Propiverine, Pyrrobutamine, Timepidium Bromide, Tridihexethyl, Tropatepine, WIN-2299, Amrutanjan, Abstral, Acetylmethadol, Acetyldihydrocodeine, Alletorphine, Anilopam, Axomadol, BC Powder, Befiradol, Benorilate, Betamethadol, Bicifadine, Butinazocine, Carbazocine, Celadrin, Chlorodyne, Cinchophen, Co-dydramol, Co-codamal, Cogazocine, Conolidine, Deltorphin I, Dezocine, Dimepheptanol, Dipyrocetyl, TRPV1 Receptor, Capsazepine, Dosulepin, Electroanalgesia, Epideral Steroid Injection, Eptazocine, Equianalgesic, Efazocine, Fedotozine, Filenadol, Fioricet, Fiorinal, Frakefamide, Hemprenorphine, 3-HM, Ibazocine, Levallorphan, Levomepromazine, Lufuradom, Magnesium Salicylate, Blue Prickly Poppy, Menabitan, A-40174, Dimethylhepylpyran, Metamizole, Metkefamide, Moramide, Morphiceptin, Moxazocine, Nafoxadol, Malmexone, Naproxen, Nefopam, Nimesulide, Naracymethadol, Norlevorphanol, Norpipanone, NS-11394, Panadol, Penthox Inhaler, Phenacetin, Phenazone, Phenazopyridine, Propyphenazone, Proxorphan, Resiniferatoxin, Rimazolium, Romifidine, RUB-A535, Salecylamide, Salonpas, Tectin, Tolfenamic Acid, Tenazocine, Ufenamate, Volazocine, Xylazine, Yangonin, Zinda Tilismath, Ziconotide, Anazocine, Bremazocine, Cyclazocine, EKC, Fluorophen, Gemazocine, Ketazocine, Metazocine, Quadazocine, Azocine, Benzazocine, 0-2545, DOU-216,303, Phenylethylpyrrolidine, GR-89696, HA-966, ICI-199,441, ICI-204,448, NNN, Nornicotine, Clemastine, PF-03654746, RTI-229, SB-269,970, U-50488, U-69,593, Bombesin, Bivaracetam, Cebaracetam, DEABL, Cromakalim, Doxapram, Dupracetam, Etiracetam, Fasoracetam, Imuracetam, Levetiracetam, Lidanserin, Nebracetam, Nefiracetam, Nicoracetam, Oxiracetam, Piperacetam, Seletracetam, MOPPP, MPBP, MPHP, MDPDP, MDPPP, Pyrovalone, a-PBP, a-PPP, Neuropeptides, Galanin, Neuropeptide Y, Enkephalin, Somatoslatin, CCK, Substance P, Neurotensin, TRH, Acepramazine, Aceprometazine, Acetanisol, Acetohexamide, Acetophenazine, Acetophenone, Acetosyringoine, 2-Acetylpyridine, Adrenalone, Anthrone, Apocynin, Avobenzone, Benzbromarone, Benziodarone, Benzoin, Butaperazine, CB-13, AM-6545, AZ-11713908, WIN-54,461, JWH-200, WIN-56,098,S-796,260, AM-1220, AM-1221, AM-1241, AM-2233, AM-630, AAI’s, CPE, GW-405,833, JWH-193, JWH-198, JWH-007, 3-Acetyl-6-Methoxybenzaldehyde, Aflobazole, AR-A000002, Azasestron, Bazinaprine, 3-Benzhydrylmorpholine, BML-190, Cobicistat, CYT387, Desmethylmoramide, Dioxaphetyl Butyrate, Edivoxetine, Epelsiban, Demoxytocin, Carbetocine, WAY-267,464, Atosiban, Eprobemide, L-371,257, L-368,899, Quinagolide, Terbutaline, 2CB-ind, 5-APDI, APICA, Donepezil, ICI-118,551, Indatraline, Indinavir, Ladostigil, Mutisianthol, PNU-99,194, S-15535, TAI, Zicronapine, Aleglitazar, Thromboxame Receptor Agonist, Verruculogen, Brevianamide, 2,5-DKP, Fellutanine, Phenylahistine, Plinabulin, Rugulosuvine, Fedrilate, Fenbutrazate, L-733,060, G-130, HC3, Indeloxazine, Levomoramide, Metostilenol, Molindone, Molracetam, Nimorazole, O-1057, O-1812, AM-2232, O-774, AM-2389, HHC, HU-243, Canbisol, Nabilone, 11-OH-THC, 2-AGE, Paxahexyl, THC-C4, AMG-36, AMG-41, AM-1235, AM-906, AM-365, O-2694, O-2372, O-2113, O-2050, VCHSR, TM-38837, PiplSB, PF-514273, MK-9470, LY-320,135, O-2545, PD-128,907, PF-219,061, ABT-670, ABT-742, UK-414,495, OSU-6162, Melanotan II, Oxaflozane, PF-592,379, 2-Phenyl-3,6-Dimethylmorpholine, Pramocaine, SCH-50911, 4-HTMPIPO, A-41988, AB-001, AB-005, ADBICA, AM-087, AM-411, KM-233, AM-679, AM-694, AM-855, AM-905, AM-919, AM-4030, AM-938, AM-251, AMG-1, AR-231,453, PSN-375,963, PSN-632,408, (C6)-CP-47,497, CCH, O-1871, CP-55,940, CP-47,497, CP-50,556’1, CP-55,244, Otenabant, (C9)-CP-47,497, CBS-0550, AVE-1625, GW-842,166x, HU-308, HU-336, HU-331, HU-320, Ajulemic Acid, JTE-7-31, A-834,735, MDA-19, S-444,823, JTE-907, JWH-015, JWH-019, JWH-030, JWH-047, JWH-048, JWH-051, JWH-057, JWH-081, SLV319, 2-Isopropyl-5-Methyl-1-(2,6-dihydroxy-4-nonphenyl)cyclohex-1-ene, HU-345, JWH-098, JWH-116, JWH-120, JWH-122, JWH-147, JWH-148, JWH-149, JWH-161, JWH-164, JWH-167, JWH-175, JWH-176, JWH-184, JWH-185, JWH-196, JWH-203, JWH-249, JWH-302, JWH-307, JWH-359, JWH-398, JWH-424, L-759,633, L-759,656, GW-405,833, Leelamine, NESS-0327, NESS-040C5, NMP-7, Nonabine, O-1125, O-1238, O-1269, O-806, O0823, Org-27569, Org-28312, LBP-1, Org-28611, Otenabant, Perrottetinene, PF-03550096, RCS-4, RCS-8, Rosonbrant, SDB-001, SDB-006, SER-601, Serinolamide A, THC-O-Phosphate, Tinabinol, VDM-11, Virohamine, A77636, Adafenoxate, Adapromine, Adatanserin, Bolmantalate, Bromantane, SR-142,948, 25B-NBOMe, 25I-NBMB, 25TFM-NBOMe, 5-MeO-NBpBiT, 2CBCB-NBOMe, 25CN-NBOH, Juncosamine, TCB-2, 6-Br-APB, Agelferin, Cridazepam, Meta-DOB, NGD-4715, Nicergoline, P7C3, SB-357,134, Sclerotia Truffle, 5-Flouro-aMT, 6-Flouro-aMT, Telepathine, AMDA, Amperozide, Cinaserin, Deramciclane, Fenanserin, Flibanserin, Glemanserin, Iferanserin, KML-010, LY-367,265, Pruvanserin, Rauwolscine, Setoperone, Spiperone, Volinanserin, Xlamidine, Altropane, ATI-2042, PIA, RTI-121, RTI-353, Tramethinib, SB-258,585, Lu-AE58054, MS-245, Ro04-6790, SB-271,046, SB-399,885, RTI-55, AC-262,356, 2′-Acetoxycocaine, Bemestron, Benzoylthiomethylecogine, Brasofesine, 2-CMT, Clobenztropine, Cocaethylene, Deptropine, Dichloropane, Diflouropine, Granisetron, 3-(p-Flourobenzoyloxy)tropane, p-ISOCOC, Methylvanillylecogonine, Norcocaine, NS-2359, RTI-126, WF-23, WF-33, WF-31, WF-11, BRL-46470, RTI-112, RTI-113, RTI-120, RTI-150, RTI-171, RTI-274, RTI-31, RTI-32, RTI-51, RTI-83, Thiophenyltropanes, MAT Inhibitor, Salicylmethylecgonine, Tesofesine, Troparil, WIN-35428, Amfonelic Acid, Oxolinc Acid, Tropisetron, Zatosetron, Dichloropane, RTI-336, RTI-126, Tropoxane, Poyo (Palm Wine), Tropicamide, Caffetin, Formic acid, Monocled Cobra, Sisa, Tramadol, Dazopride, Dolasetron, Amylocaine, Articaine, Bupivacaine, Butacaine, Chloroprocaine, Cyclomethycaine, Etidocaine, Hexylcaine, Levobupivacaine, Mepivacaine, Meprylcaine, Prilocaine, Proxymetacaine, Risocaine, Ropivacaine, Tetracaine, Trimecaine, Piperocaine, Metabutoxycaine, Adipiplon, Almitrine, ARRY-520, AZD5423, Cisapride, CP-226,269, CRL-40,941, DBL-583, Dexamethasone, DFMD, Methyldopa, Carbidopa, d-DOPA, L-DOPS, Octaflourocyclobutane, DFB, Didesmethylcitalopram, Elopiprazole, Phenylpiprazine, F-15,599, FGIN-127, Fletazepam, Flucindole, GR-159,897, LY-503,430, MPPF, PEPA, RS-127,445, S-23, SHA-68, SNAP-7941, SNAP-94847, TP-003, TPA-023, UH-301, Calycosin, Flavinoids, Psi-Tectorigenin, Blochanin A, Formononetin, Glyciten, Irigenin, Methoxyisoflavone, 5-O-Methylgenistein, 7-O-Methylluteone, Ononin, Pratensein, Prunetin, Retusin, Tectoridin, Tectorigenin, Barbigerone, Daidzein, Derrubone, Genistein, Ipriflavone, Irilone, Luteone, Orobol, Psuedobaotigenin, Wighteone, AMG-3, Nabazenil, Naboctate, a-Napthoflavone, 11-Nor-9-Carboxy-THC, Pirnabine, Apiol, Dillapiol, 1,3-Benzodioxole, Piperonal, beta-Asarone, Eleicin, Homovanyllyl Alcohol, Myristicin, 2-Bromo-4,5-Methylenedioxyamphetamine, Californidine, Chavicine, Cinoxacin, Dibutylone, Fenoverine, Befuraline, MDIP, MDMAI, MDPR, MDAL, ORTHO-MDA, MDP1P, MDP2P, Omiloxetine, Osemozotan, Piclozotan, Robalzotan, Ebalzotan, Sarlzotan, Piperine, Protokylol, Isoprenaline, Rhoeadine, MDMPEA, MMDPEA, MMDMPEA, MDIP, MDHOET, MDPL, GYKI-52895, Ungiminorine, NADA, Methylene blue, ECG, EGCG, EGC, Levonantradol, Cone Snail Venom, A-836,339, Abacavir, CYP-LAD, 2-Bromo-LSD, BU-LAD, DAM-57, DAL, Epicriptine, Ergometrine, Ergometrinine, Ergostine, ETH-LAD, LEA-32, Methylergometrine, MLD-41, LSP, LSH, MIPLA, PARGY-LAD, PRO-LAD, DCG-IV, DOV-102,677, MDCPM, MNTX, Amfonelic acid, J-113,397, SB-612,111, VUF-6002, DBM, Piberatine, Ilercimide, Dithranol, Divaplon, Ebastine, Flopropione, Iloperidone, Ketorolac, Melperone, NNC-38-1044, Tetralone, Cuscohydrine, Hygrine, 4-NEMD, Aceburic Acid, Amfecloral, Aprobarbital, Arfendazam, Benzobarbital, Benzylbutylbarbituate, Brallobarbital, Brophebarbital, Buthalitol, Carbubarb, Climazolam, Cyclobarbital, Cyclopentobarbital, and Acid (i.e. regular LSD).

(source)

Harmonic Society (1/4): Art as Family Resemblance + Cool Kid Theory

Note – The full essay’s title is: Harmonic Society: 8 Models of Art for a Scientific Paradigm of Aesthetic Qualia

The following essay was recently published in the Berlin-based art magazine Art Against Art (issue).

The essay offers 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.

Below you will find the abstract, introduction, and the first 2 (out of 8) models of art. I will be sharing 2 new models each week until I’ve shared all 8 of them.



Contemporary writing about art is in exactly the same place as writing about nature was before Darwin came along. Before Darwin there was no single intellectual matrix upon which to fix all of these impressions and ideas. There was no way of organizing all of that information. And this seems to me to be the situation we are in with the arts, as well.

 

– Brian Eno, “What is Art Actually For?” (2012)

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 neuronal 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.

Introduction

We shall start this essay by making the assumption that there are real and substantial stakes when it comes to art. Not all of my readers will agree with this point, and those who do might in fact secretly worry that they are overvaluing art for selfish reasons. I come here to suggest that there could be very real and substantial stakes in art, and that to realize this you do not need to buy into sentimentalism, fanaticism, wishful thinking, or traditionalist attitudes. You could start with the sheer amount of human attention that is devoted to art in one way or another. Art seems to make a lot of people do things, and do them with a lot of their energy and focus. Indeed, many people point at their intimations with art as personally defining moments. Some say their best self is expressed in their creation, consumption, or participation in art. So what is all of this fuss about?

Alas, most things of grand significance have been analyzed by countless people. The sheer magnitude of certain human activity is not a justification for caring about it at the margin, considering the often corresponding sheer magnitude of other people already analyzing and scientifically probing the field. That is, of course, unless you have a reason to think that you have something that everyone else has been missing all this time. And this is the case for you and me right now. The new perspectives on art on this essay come from thinking very deeply about consciousness, qualia, and the possible implementations of the pleasure-pain axis, aka. valence. We will see how investigating these questions cashes out in novel insights about art. In turn, these models, as well as the empirically testable predictions they generate, might have the ability to reframe what is going on with art in a way that allows us to predict how and when it will bring about good and desirable effects.

The 8 Models

  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 mess with the energy parameter of your mind ()
  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).

Models 1 through 4 are already present in the memetic ecosystem of today. They focus on external aspects of art, such as why it reproduces and how it impacts social behavior. From the point of view of Marr’s levels of analysis, these four models focus on the behavioral/computational level of analysis.[1] Namely, what art looks like from the outside, and how it reproduces. Models 5 through 8 are novel perspectives that arise out of examining artistic experiences in light of Marr’s algorithmic and implementation-level accounts of consciousness. That is, how the internal information-processing and implementational features of brains give rise to art. In turn, these four models give rise to a new understanding for when art does or does not do its job.

1. Semantic Deflation

This model says that asking “what is art?” is, more often than not, an utterly confused question. Perhaps in antiquity it would make sense to talk about the essence of art, expecting there to be a set of necessary and sufficient conditions for something to be art. According to the semantic deflation model of art, starting out with the expectation of finding a crisp set of requirements for something to be art is starting off on the wrong foot, for believing that there is an essence of art is to simply not pay attention to the large set of inconsistent use cases for that word, which challenges the existence of such an essence.

The semantic deflation model is supported by key insights from 20th Century philosophy of language, such as found in the works of Russell, Frege, Carnap, Quine, and especially those of the late Wittgenstein. Of particular relevance when it comes to defining art we could point at Wittgenstein’s concept of family resemblance. Developed in his book Philosophical Investigations, the concept of family resemblance posits that many words which seem at first to point at something with a core essence are, in fact, pointing to referents which have overlapping similarities but no universally shared attributes.

Like the concept of a game, which refers to activities as diverse as checkers and cellular automata, and which cannot be easily defined in terms of e.g. point systems, physical movement, number of players, etc., we likewise cannot expect art to be definable in terms of media, intent, social effects, or craft. All we can aspire to is to identify common and characteristic features.

According to this view, the models of art that take objective beauty seriously on Platonic or traditionalist grounds are fundamentally misguided. Callbacks to retraditionalize society to preserve its past – more genuine – aesthetics are perceived as parodies of themselves, trying to undo an intrinsically irreversible process of cultural learning. Nowadays few people seriously believe that art should be conceived of as a tool exclusively for the glorification of traditional values and religious symbolism. It is also not fashionable to think of art in sincere non-ironic ways. Those who wish to earnestly engage with art must remind themselves that the days in which its meaning could be grounded on universally agreed definitions is gone.

Although sobering and clarifying, I argue that this view leaves a lot of value on the table. Sure, art has no common essence, but that does not mean that all of the uses of the word are pointing at things of equal value. Semantic deflation does not provide us with guidance for identifying and promoting good art. Indeed, as Wittgenstein might put it, “[p]hilosophy may in no way interfere with the actual use of language, it can in the end only describe it. For it cannot give it any foundation either. It leaves everything as it is.” (Philosophical Investigations, pg.49).

Interestingly, the semantic deflation model of art can itself be conceived of as an aesthetic. This aesthetic rewards those who can help others transcend narrow conceptions of what art is. Exemplary movements like Dadaism and Pop Art could be thought of as pushing the aesthetic of semantic deflation to the limit.

Art is what you can get away with.” – Andy Warhol.

But what if there is something worth preserving, reifying, and defining clearly in art? Semantic deflation should perhaps be thought of as a first step in figuring out what is valuable about art, rather than a final destination. To move beyond it, one should avoid reviving a naïve essentialist view of art, and instead identify conceptual focal points that genuinely enrich our conception of art. Rather than destroying preconceptions, we could instead refactor, discover, and build new and enlightened ones. Transcending absolutist deflationary views of art is indeed more appealing when there is an alternative in sight that is both better and more real than what you get by merely deconstructing and breaking down naïve views. And this is what we will attempt to do as we move on to other models of art.

2. Cool Kid Theory

In his book “The Mating Mind”, Geoffrey Miller discusses art in light of evolutionary psychology. In this view, art, rather than being a thing, is a culturally sanctioned activity devised to allow people to display their genetic fitness, by showing off above-average features of their phenotypes. Art is, in this view, at its core, an outlet for courtship. Incredible performances like those of Liszt and Rachmaninoff are not just for the pleasure of music. The incredible difficulty of performing the musical compositions is itself the show. The difficulty is not a side-effect of discovering new soundscape frontiers that produce blissful and extraordinary experiences to degrees that couldn’t be possible without the difficulty of execution. Rather, the difficulty of performing the musical pieces is part and parcel of what makes them so extraordinary. They are indeed erotic displays of fitness traits (cf. Lisztomania) crafted to cause an impression in fertile ground.

Indeed, we are constructed in such a way that we can emotionally hack and be hacked by others to assess each others’ suitability as potential family, friends, and neighbors. Unfakeable fitness displays typically require prodigious amounts of waste. As Geoffrey puts it: “Every sexual ornament in every sexually reproducing species could be viewed as a different style of waste.” (The Mating Mind, pg. 128. cf. An Infinite Variety of Waste) Only extremely fit organisms can afford to spend resources on non-survival tasks.

Fashion, too, in this light, is a sort of collective activity of systematic waste. Keeping up with the latest trends shows that you have a lot of free time (which, contrary to popular belief, is perceived as more sexy than the alternative). Only the wealthy, disciplined, or well-organized can manage to sustain energy- and time-consuming hobbies for years and years.

This theory of art has a problem, though, which is that on its own it does not explain art as a cultural institution. We could very well imagine that aesthetics-based displays of genetic fitness would be circumscribed to individual efforts but in practice we see groups of people coming together to work out the potentialities, possibilities, limits, and implications of particular aesthetics. We don’t only generate extraordinarily wasteful works of art ourselves, but do so contextually within art movements and aesthetic languages. Why is this?

I believe there is a layer of organization above individual signaling displays. To fully grasp it, we need to talk about what I have named “Cool Kid Theory”. This theory postulates that above-average and particularly well-rounded individuals, aka. Cool Kids, figure out ways of enticing others to show their peacock feathers, so to speak. Being a Cool Kid is not to excel oneself, but rather, to have the precise kind of strategic mediocrity that gives others the urge to show how they can improve upon your craft. At its extreme, a Cool Kid commands a group of people who practice a particular type of craft, which ultimately becomes an artistic gang. If you are a Cool Kid you can decide who is cool and who is not by choosing what challenges to measure the performance of people with.

Who wants to be a Cool Kid? The answer is, for the most part, anyone who can get away with it. It is so evolutionarily adaptive to be a Cool Kid that we have a number of psychological programs that can be triggered with a sequence of social cues that can make almost anyone into a Cool Kid.

Part and parcel of being a Cool Kid is to know how to induce the fear of missing out in others. It is about detecting when a particular challenge is headed towards an imminent dead end and course-correct to keep people engaged.

Here is an example. If you ever encounter a group of dancers in public transportation, you will notice that there is a Cool Kid who binds them together. The Cool Kid selects for people who have unique talents, and collectively accumulates a solidly impressive bag of tricks. Everyone in the group takes turns showing their best trick. For instance, the group might have someone who sings, someone who plays an instrument, and someone who owns a subwoofer (sometimes that’s all it takes). You might also see that there is a guy who can do the weird elbow twist thingy, the one who can break dance and do nine spins on his back, the one who can beat-box to the tune of the song, and the one who moonwalks while playing a harmonica. An effective Cool Kid is one who can corral all of these specialists and be the artistic glue who controls the overarching aesthetic. And this aesthetic is what defines a set of challenges used for impressive fitness displays.

The art world can be thus conceived of as a large super-cluster of Cool Kid gangs cornering the economy of attention. The competitive nature of Cool Kids is sure to produce a constant stream of novel stimuli, endlessly varied trends and fashions, as well as competitive and indeed sometimes even virulent attacks between aesthetics. For he who controls the aesthetic, controls your ability to be popular.

To be continued…



[1] Marr’s levels of analysis is a framework to analyze information-processing systems. First we have the computational level, which describes what the system does from a third-person point of view. This level is concerned with questions like what the system is capable of, and how quickly it can succeed at it. Second is the algorithmic level of analysis, which focuses on the internal representations and operations used to transform the inputs into the outputs. And third is the implementation level of analysis, which is concerned with the physical realization of the algorithms described in the second level.

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.

Logarithmic Scales of Pleasure and Pain: Rating, Ranking, and Comparing Peak Experiences Suggest the Existence of Long Tails for Bliss and Suffering

TL;DR

Based on: the characteristic distribution of neural activity, personal accounts of intense pleasure and pain, the way various pain scales have been described by their creators, and the results of a pilot study we conducted which ranks, rates, and compares the hedonic quality of extreme experiences, we suggest that the best way to interpret pleasure and pain scales is by thinking of them as logarithmic compressions of what is truly a long-tail. The most intense pains are orders of magnitude more awful than mild pains (and symmetrically for pleasure).

This should inform the way we prioritize altruistic interventions and plan for a better future. Since the bulk of suffering is concentrated in a small percentage of experiences, focusing our efforts on preventing cases of intense suffering likely dominates most utilitarian calculations.

An important pragmatic takeaway from this article is that if one is trying to select an effective career path, as a heuristic it would be good to take into account how one’s efforts would cash out in the prevention of extreme suffering (see: Hell-Index), rather than just QALYs and wellness indices that ignore the long-tail. Of particular note as promising Effective Altruist careers, we would highlight working directly to develop remedies for specific, extremely painful experiences. Finding scalable treatments for migraines, kidney stones, childbirth, cluster headaches, CRPS, and fibromyalgia may be extremely high-impact (cf. Treating Cluster Headaches and Migraines Using N,N-DMT and Other Tryptamines, Using Ibogaine to Create Friendlier Opioids, and Frequency Specific Microcurrent for Kidney-Stone Pain). More research efforts into identifying and quantifying intense suffering currently unaddressed would also be extremely helpful. Finally, if the positive valence scale also has a long-tail, focusing one’s career in developing bliss technologies may pay-off in surprisingly good ways (whereby you may stumble on methods to generate high-valence healing experiences which are orders of magnitude better than you thought were possible).

Contents

Introduction:

  1. Weber’s Law
  2. Why This Matters

General ideas:

  1. The Non-Linearity of Pleasure and Pain
    1. Personal Accounts
    2. Consciousness Expansion
    3. Peak Pleasure States: Jhanas and Temporal Lobe Seizures
    4. Logarithmic Pain Scales: Stings, Peppers, and Cluster Headaches
  2. Deference-type Approaches for Experience Ranking
    1. Normal World vs. Lognormal World
    2. Predictions of Lognormal World

Survey setup:

  1. Mechanical Turk
  2. Participant Composition
  3. Filtering Bots

Results:

  1. Appearance Base Rates
  2. Average Ratings
  3. Deference Graph of Top Experiences
    1. Rebalanced Smoothed Proportion
    2. Triadic Analysis
  4. Latent Trait Ratings
  5. Long-tails in the Responses to “How Many Times Better/Worse” Question

Discussion:

  1. Key Pleasures Surfaced
    1. Birth of Children
    2. Falling in Love
    3. Travel/Vacation
    4. MDMA/LSD/Psilocybin
    5. Games of Chance Earnings
  2. Key Pains
    1. Kidney Stones/Migraines
    2. Childbirth
    3. Car Accidents
    4. Death of Father and Mother
  3. Future Directions for Methodological Approaches
    1. Graphical Models with Log-Normal Priors
  4. Closing Thoughts on the Valence Scale
  5. Additional Material
    1. Dimensionality of Pleasure and Pain
    2. Mixed States
    3. Qualia Formalism
  6. Notes

Introduction

Weber’s Law

Weber’s Law describes the relationship between the physical intensity of a stimulus and the reported subjective intensity of perceiving it. For example, it describes the relationship between how loud a sound is and how loud it is perceived as. In the general case, Weber’s Law indicates that one needs to vary the stimulus intensity by a multiplicative fraction (called “Weber’s fraction”) in order to detect a just noticeable difference. For example, if you cannot detect the differences between objects weighing 100 grams to 105 grams, then you will also not be able to detect the differences between objects weighing 200 grams to 210 grams (implying the Weber fraction for weight perception is at least 5%). In the general case, the senses detect differences logarithmically.

There are two compelling stories for interpreting this law:

In the first story, it is the low-level processing of the senses which do the logarithmic mapping. The senses “compress” the intensity of the stimulation and send a “linearized” packet of information to one’s brain, which is then rendered linearly in one’s experience.

In the second story, the senses, within the window of adaptation, do a fine job of translating (somewhat) faithfully the actual intensity of the stimulus, which then gets rendered in our experience. Our inability to detect small absolute differences between intense stimuli is not because we are not rendering such differences, but because Weber’s law applies to the very intensity of experience. In other words, the properties of one’s experience could follow a long-tail distribution, but our ability to accurately point out differences between the properties of experiences is proportional to their intensity.

We claim that, at least for the case of valence (i.e the pleasure-pain axis), the second story is much closer to the truth than the first. Accordingly, this article rethinks the pleasure-pain axis (also called the valence scale) by providing evidence, arguments, and datapoints to support the idea that how good or bad experiences feel follows a long-tail distribution.

As an intuition pump for what is to follow, we would like to highlight the empirical finding that brain activity follows a long-tail distribution (see: Statistical Analyses Support Power Law Distributions Found in Neuronal Avalanches, and Logarithmic Distributions Prove that Intrinsic Learning is Hebbian). The story where the “true valence scale” is a logarithmic compression is entirely consistent with the empirical long-tails of neural activity (in which “neural avalanches” account for a large fraction of overall brain activity).

The concrete line of argument we will present is based on the following:

  1. Phenomenological accounts of intense pleasure and pain (w/ accounts of phenomenal time and space expansion),
  2. The way in which pain scales are described by those who developed them, and
  3. The analytic results of a pilot study we conducted which investigates how people rank, rate, and assign relative proportions to their top 3 best and worst experiences

Why This Matters

Even if you are not a strict valence utilitarian, having the insight that the valence scale is long-tailed is still very important. Most ethical systems do give some weight to the prevention of suffering (in addition to the creation of subjectively valuable experiences), even if that is not all they care about. If your ethical system weighted slightly the task of preventing suffering when believing in a linear valence scale, then learning about the long-tailed nature of valence should in principle cause a major update. If indeed the worst experiences are exponentially more negative than originally believed by one’s ethical system, which nonetheless still cared about them, then after learning about the true valence scale the system would have to reprioritize. We suggest that while it might be unrealistic to have every ethical system refocus all of its energies on the prevention of intense suffering (and subsequently on researching how to create intense bliss sustainably), we can nonetheless expect such systems to raise this goal on their list of priorities. In other words, while “ending all suffering” will likely never be a part of most people’s ethical system, we hope that the data and arguments here presented at least persuade them to add “…and prevent intense forms of suffering” to the set of desiderata.

Indeed, lack of awareness about the long-tails of bliss and suffering may be the cause of an ongoing massive moral catastrophe (notes by Linch). If indeed the degree of suffering present in experiences follows a long-tail distribution, we would expect the worst experiences to dominate most utilitarian calculus. The biggest bang for the buck in altruistic interventions would therefore be those that are capable of directly addressing intense suffering and generating super-bliss.

General Ideas

The Non-Linearity of Pleasure and Pain

true_pleasure_scale

True long-tail pleasure scale (warning: psychedelics increase valence variance – the values here are for “good/lucky” trips and there is no guarantee e.g. LSD will feel good on a given occasion). Also: Mania is not always pleasant, but when it is, it can be super blissful.

true_pain_scale

True long-tail pain scale

As we’ve briefly discussed in previous articles (1, 2, 3), there are many reasons to believe that both pleasure and pain can be felt along a spectrum with values that range over possibly orders of magnitude. Understandably, someone who is currently in a state of consciousness around the human median of valence is likely to be skeptical of a claim like “the bliss you can achieve in meditation is literally 100 times better than eating your favorite food or having sex.” Intuitively, we only have so much space in our experience to fit bliss, and when one is in a “normal” or typical state of mind for a human, one is forced to imagine “ultra blissful states” by extrapolating the elements of one’s current experience, which certainly do not seem capable of being much better than, say, 50% of the current level of pleasure (or pain). The problem here is that the very building blocks of experiences that enable them to be ultra-high or ultra-low valence are themselves necessary to imagine accurately how they can be put together. Talking about extreme bliss to someone who is anhedonic is akin to talking about the rich range of possible color experiences to someone who is congenitally fully colorblind (cf. “What Mary Didn’t Know“).

“Ok”, you may say, “you are just telling me that pleasure and pain can be orders of magnitude stronger than I can even conceive of. What do you base this on?”. The most straightforward way to be convinced of this is to literally experience such states. Alas, this would be deeply unethical when it comes to the negative side, and it requires special materials and patience for the positive side. Instead, I will provide evidence from a variety of methods and conditions.

Personal Accounts

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I’ve been lucky to not have experienced major pain in my life so far (the worst being, perhaps, depression during my teens). I have, however, had two key experiences that gave me some time to introspect on the non-linear nature of pain. The first one comes from when I accidentally cut a super-spicy pepper and touched it with my bare hands (the batch of peppers I was cutting were mild, but a super-hot one snuck into the produce box). After a few minutes of cutting the peppers, I noticed that a burning heat began to intensify in my hands. This was the start of experiencing “hot pepper hands” for a full 8 hours (see other people’s experiences: 1, 2, 3). The first two to three hours of this ordeal were the worst, where I experienced what I rated as a persistent 4/10 pain interspersed with brief moments of 5/10 pain. The curious thing was that the 5/10 pain moments were clearly discernible as qualitatively different. It was as if the very numerous pinpricks and burning sensations all over my hands were in a somewhat disorganized state most of the time, but whenever they managed to build-up for long enough, they would start clicking with each other (presumably via phase-locking), giving rise to resonant waves of pain that felt both more energetic, and more aversive on the whole. In a way, this jump from what I rated as 4/10 to 5/10 was qualitative as well as quantitative, and it gave me some idea of how something that is already bad can become even worse.

My second experience involves a mild joint injury I experienced while playing Bubble Soccer (a very fun sport no doubt, and a common corporate treat for Silicon Valley cognotariats, but according to my doctor it is also a frequent source of injuries among programmers). Before doing physical therapy to treat this problem (which mostly took care of it), I remember spending hours introspecting on the quality of the pain in order to understand it better. It wasn’t particularly bad, but it was constant (I rated it as 2/10 most of the time). What stuck with me was how its constant presence would slowly increase the stress of my entire experience over time. I compared the experience to having an uncomfortable knot stuck in your body. If I had a lot of mental and emotional slack early in the day, I could easily take the stress produced by the knot and “send it elsewhere” in my body. But since the source of the stress was constant, eventually I would run out of space, and the knot would start making secondary knots around itself, and it was in those moments where I would rate the pain at a 3/10. This would only go away if I rested and somehow “reset” the amount of cognitive and emotional slack I had available.

The point of these two stories is to highlight the observation that there seem to be phase-changes between levels of discomfort. An analogy I often make is with the phenomenon of secondary coils when you twist a rope. The stress induced by pain- at least introspectively speaking- is pushed to less stressed areas of your mind. But this has a limit, which is until your whole world-simulation is stressed to the point that the source of stress starts creating secondary “stress coils” on top of the already stressed background experience. This was a very interesting realization to me, which put in a different light weird expressions that chronic pain patients use like “my pain now has a pain of its own” or “I can’t let the pain build up”.

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DNA coils and super-coils as a metaphor for pain phase-changes?

Consciousness Expansion

What about more extreme experiences? Here we should briefly mention psychedelic drugs, as they seem to be able to increase the energy of one’s consciousness (and in some sense “multiply the amount of consciousness“) in a way that grows non-linearly as a function of the dose. An LSD experience with 100 micrograms may be “only” 50% more intense than normal everyday life, but an LSD experience with 200 micrograms is felt as 2-3X as intense, while 300 micrograms may increase the intensity of experience by perhaps 10X (relative to normal). Usually people say that high-dose psychedelic states are indescribably more real and vivid than normal everyday life. And then there are compounds like 5-MeO-DMT, which people often describe as being in “a completely different category”, as it gives rise to what many describe as “infinite consciousness”. Obviously there is no such thing as an experience with infinite consciousness, and that judgement could be explained in terms of the lack of “internal boundaries” of the state, which gives the impression of infinity (not unlike how the surface of a torus can seem infinite from the point of view of a flatlander). That said, I’ve asked rational and intelligent people who have tried 5-MeO-DMT in non-spiritual settings what they think the intensity of their experiences was, and they usually say that a strong dose of 10mg or more gives rise to an intensity and “quantity” of consciousness that is at least 100X as high as normal everyday experiences. There are many reasons to be skeptical of this, no doubt, but the reports should not be dismissed out of hand.

Antoine's_Necklace_Iteration_2

Secondary knots and links as a metaphor for higher bliss

As with the above example, we can reason that one of the ways in which both pain and pleasure can be present in *multiples* of one’s normal hedonic range is because the amount of consciousness crammed into a moment of experience is not a constant. In other words, when someone in a typical state of consciousness asks “if you say one can experience so much pain/pleasure, tell me, where would that fit in my experience? I don’t see much room for that to fit in here”, one can respond by saying that “in other states of consciousness there is more (phenomenal) time and space within each moment of experience”. Indeed, at Qualia Computing we have assembled and interpreted a large number of experiences of high-energy states of consciousness that indicate that both phenomenal time, and phenomenal space, can drastically expand. To sum it up – you can fit so much pleasure and pain in peak experiences precisely because such experiences make room for them.

Let us now illustrate the point with some paradigmatic cases of very high and vey low valence:

Peak Pleasure States: Jhanas and Temporal Lobe Seizures

On the pleasure side, we have Buddhist meditators who experience meditative states of absorption (aka. “Jhanas”) as extremely, and counter-intuitively, blissful:

The experience can include some very pleasant physical sensations such as goose bumps on the body and the hair standing up to more intense pleasures which grow in intensity and explode into a state of ecstasy. If you have pain in your legs, knees, or other part of the body during meditation, the pain will actually disappear while you are in the jhanas. The pleasant sensations can be so strong to eliminate your painful sensations. You enter the jhanas from the pleasant experiences exploding into a state of ecstasy where you no longer “feel” any of your senses.

9 Jhanas, Dhamma Wiki

There are 8 (or 9, depending on who you ask) “levels” of Jhanas, and the above is describing only the 1st of them! The higher the Jhana, the more refined the bliss becomes, and the more detached the state is from the common referents of our everyday human experience. Ultra-bliss does not look at all like sensual pleasure or excitement, but more like information-theoretically optimal configurations of resonant waves of consciousness with little to no intentional content (cf. semantically neutral energy). I know this sounds weird, but it’s what is reported.

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“Streamlines from the insula to the cortex” – the insula (in red) is an area of the brain intimately implicated in the super-bliss that sometimes precedes temporal lobe epilepsy (source)

Another example I will provide about ultra-bliss concerns temporal lobe epilepsy, which in a minority of sufferers gives rise to extraordinarily intense states of pleasure, or pain, or both. Such experiences can result in Geschwind syndrome, a condition characterized by hypergraphia (writing non-stop), hyper-religiosity, and a generally intensified mental and emotional life. No doubt, any experience that hits the valence scale at one of its extremes is usually interpreted as other-worldly and paranormal (which gives rise to the question of whether valence is a spiritual phenomenon or the other way around). Famously, Dostoevsky seems to have experienced temporal lobe seizures, and this ultimately informed his worldview and literary work in profound ways. Here is how he describes them:

“A happiness unthinkable in the normal state and unimaginable for anyone who hasn’t experienced it… I am then in perfect harmony with myself and the entire universe.”

 

– From a letter to his friend Nikolai Strakhov.

“I feel entirely in harmony with myself and the whole world, and this feeling is so strong and so delightful that for a few seconds of such bliss one would gladly give up 10 years of one’s life, if not one’s whole life. […] You all, healthy people, can’t imagine the happiness which we epileptics feel during the second before our fit… I don’t know if this felicity lasts for seconds, hours or months, but believe me, I would not exchange it for all the joys that life may bring.”

 

– from the character Prince Myshkin in Dostoevsky’s novel, The Idiot, which he likely used to give a voice to his own experiences.

Dostoevsky is far from the only person reporting these kinds of experiences from epilepsy:

As Picard [a scientist investigating seizures] cajoled her patients to speak up about their ecstatic seizures, she found that their sensations could be characterised using three broad categories of feelings (Epilepsy & Behaviour, vol 16, p 539). The first was heightened self-awareness. For example, a 53-year-old female teacher told Picard: “During the seizure it is as if I were very, very conscious, more aware, and the sensations, everything seems bigger, overwhelming me.” The second was a sense of physical well-being. A 37-year-old man described it as “a sensation of velvet, as if I were sheltered from anything negative”. The third was intense positive emotions, best articulated by a 64-year-old woman: “The immense joy that fills me is above physical sensations. It is a feeling of total presence, an absolute integration of myself, a feeling of unbelievable harmony of my whole body and myself with life, with the world, with the ‘All’,” she said.

 

– from “Fits of Rapture”, New Scientist (January 25, 2014) (source)

All in all, these examples illustrate the fact that blissful states can be deeper, richer, more intense, more conscious, and qualitatively superior to the normal everyday range of human emotion.

Now, how about the negative side?

Logarithmic Pain Scales: Stings, Peppers, and Cluster Headaches

“The difference between 6 and 10 on the pain scale is an exponential difference. Believe it or not.”

Insufferable Indifference, by Neil E. Clement (who experiences chronic pain ranging between 6/10 to 10/10, depending on the day)

Three pain-scale examples that illustrate the non-linearity of pain are: (1) the Schmidt sting pain index, (2) the Scoville scale, and (3) the KIP scale:

image

(1) Justin O. Schmidt stung himself with over 80 species of insects of the Hymenoptera order, and rated the ensuing pain on a 4-point-scale. About the scale, he had to say the following:

4:28 – Justin Schmidt: The harvester ant is what got the sting pain scale going in the first place. I had been stung by honeybees, yellow jackets, paper wasps, etc. the garden variety stuff, that you get bitten by various beetles and things. I went down to Georgia, which has the Eastern-most extension of the harvester ant. I got stung and I said “Wooooow! This is DIFFERENT!” You know? I thought I knew everything there was about insect stings, I was just this dumb little kid. And I realized “Wait a minute! There is something different going on here”, and that’s what got me to do the comparative analysis. Is this unique to harvester ants? Or are there others that are like that. It turns out while the answer is, now we know much later – it’s unique! [unique type of pain]. 

[…]

7:09 – Justin Schmidt: I didn’t really want to go out and get stung for fun. I was this desperate graduate student trying to get a thesis, so I could get out and get a real job, and stop being a student eventually. And I realized that, oh, we can measure toxicity, you know, the killing power of something, but we can’t measure pain… ouch, that one hurts, and that one hurts, and ouch that one over there also hurts… but I can’t put that on a computer program and mathematically analyze what it means for the pain of the insect. So I said, aha! We need a pain scale. A computer can analyze one, two, three, and four, but it can’t analyze “ouch!”. So I decided that I had to make a pain scale, with the harvester ant (cutting to the chase) was a 3. Honey bees was a 2. And I kind of tell people that each number is like 10 equivalent of the number before. So 10 honey bee stings are equal to 1 harvester ant sting, and 10 harvester ant stings would equal one bullet ant sting.

[…]

11:50 – [Interviewer]: When I finally worked up the courage to [put the Tarantula Hawk on my arm] and take this sting. The sting of that insect was electric in nature. I’ve been shocked before, by accidentally taking a zap from an electrical cord. This was that times 10. And it put me on the ground. My arm seized up from muscle contraction. And it was probably the worst 5 minutes of my life at that point.

Justin Schmidt: Yeah, that’s exactly what I call electrifying. I say, imagine you are walking along in Arizona, and there is a wind storm, and the power line above snaps the wire, and it hits you, of course that hasn’t happened to me, but that’s what you imagine it feels like. Because it’s absolutely electrifying, I call it debilitating because you want to be macho, “ah I’m tough, I can do this!” Now you can’t! So I tell people lay down and SCREAM! Right?

[Interviewer]: That’s what I did! And Mark would be like, this famous “Coyote, are you ok? Are you ok?”

Justin Schmidt: No, I’m not ok!

[Interviewer]: And it was very hard to try to compose myself to be like, alright, describe what is happening to your body right now. Because your mind goes into this state that is like blank emptiness. And all you can focus on is the fact that there’s radiating pain coming out of your arm.

Justin Schmidt: That’s why you scream, because now you’re focusing on something else. In addition to the pain, you’re focusing on “AAAAAAHHHHH!!!” [screams loudly]. Takes a little bit of the juice off of the pain, so maybe you lower it down to a three for as long as you can yell. And I can yell for a pretty long time when I’m stung by a tarantula hawk.

 

Origin of STINGS!, interview of Justin O. Schmidt

If we take Justin’s word for it, a sting that scores a 4 on his pain scale is about 1,000 times more painful than a sting that scores a 1 on his scale. Accordingly, Christopher Starr (who replicated the scale), stated that any sting that scores a 4 is “traumatically painful” (source). Finally, since the scale is restricted to stings of insects of the Hymenoptera order, it remains possible that there are stings whose pain would be rated even higher than 4. A 5 on the sting pain index might perhaps be experienced with the stings of the box jellyfish that produces Irukandji syndrome, and the bite of the giant desert centipede. Needless to say, these are to be avoided.

Moving on…

(2) The Scoville scale measures how spicy different chili peppers and hot sauces are. It is calculated by diluting the pepper/sauce in water until it is no longer possible to detect any spice in it. The number that is associated with the pepper or sauce is the ratio of water-to-sauce that makes it just barely possible to taste the spice. Now, this is of course not itself a pain scale. I would nonetheless anticipate that taking the log of the Scoville units of a dish might be a good approximation for the reported pain it delivers. In particular, people note that there are several qualitative jumps in the type and nature of the pain one experiences when eating hot sauces of different strengths (e.g. “Fuck you Sean! […] That was a leap, Sean, that was a LEAP!” – Ken Jeong right after getting to the 135,000 Scoville units sauce in the pain porn Youtube series Hot Ones). Amazon reviews of ultra-hot sauces can be mined for phenomenological information concerning intense pain, and the general impression one gets after reading such reviews is that indeed there is a sort of exponential range of possible pain values:

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I know it may be fun to trivialize this kind of pain, but different people react differently to it (probably following a long-tail too!). For some people who are very sensitive to heat pain, very hot sauce can be legitimately traumatizing. Hence I advise against having ultra-spicy sauces around your house. The novelty value is not worth the probability of a regrettable accident, as exemplified in some of the Amazon reviews above (e.g. a house guest assuming that your “Da’Bomb – Beyond Insanity” bottle in the fridge can’t possibly be that hot… and ending up in the ER and with PTSD).

I should add that media that is widely consumed about extreme hot sauce (e.g. the Hot Ones mentioned above and numerous stunt Youtube channels) may seem fun on the surface, but what doesn’t make the cut and is left in the editing room is probably not very palatable at all. From an interview: “Has anyone thrown up doing it?” (interviewer) – “Yeah, we’ve run the gamuts. We’ve had people spit in buckets, half-pass out, sleep in the green room afterwards, etc.” (Sean Evans, Hot Ones host). T.J. Miller, when asked about what advice he would give to the show while eating ultra-spicy wings, responded: “Don’t do this. Don’t do this again. End the show. Stop doing the show. That’s my advice. This is very hot. This is painful. There’s a problem here.”

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Trigeminal Neuralgia pain scale – a condition similarly painful to Cluster Headaches

(3) Finally, we come to the “KIP scale”, which is used to rate Cluster Headaches, one of the most painful conditions that people endure:

The KIP scale

KIP-0 No pain, life is beautiful
KIP-1 Very minor, shadows come and go. Life is still beautiful
KIP-2 More persistent shadows
KIP-3 Shadows are getting constant but can deal with it
KIP-4 Starting to get bad, want to be left alone
KIP-5 Still not a “pacer” but need space
KIP-6 Wake up grumbling, curse a bit, but can get back to sleep without “dancing”
KIP-7 Wake up, sleep not an option, take the beast for a walk and finally fall into bed exhausted
KIP-8 Time to scream, yell, curse, head bang, rock, whatever works
KIP-9 The “Why me?” syndrome starts to set in
KIP-10 Major pain, screaming, head banging, ER trip. Depressed. Suicidal.

The duration factor is multiplied by the intensity factor, which uses the KIP scale in an exponential way – a KIP 10 is not just twice as bad as a KIP 5, it’s ten times as intense.

Source: Keeping Track, by Cluster Busters

As seen above, the KIP scale is acknowledged by its creator and users to be logarithmic in nature.

In summary: We see that pleasure comes in various grades and that peak experiences such as those induced by psychedelics, meditation, and temporal lobe seizures seem to be orders of magnitude more energetic and better than everyday sober states. Likewise, we see that across several categories of pain, people report being surprised by the leaps in both quality and intensity that are possible. More so, at least in the case of the Schmidt Index and the Kip Scale, the creators of the scale were explicit that it was a logarithmic mapping of the actual level of sensation.

While we do not have enough evidence (and conceptual clarity) to assert that the intensity of pain and pleasure does grow exponentially, the information presented so far does suggest that the valence of experiences follows a long-tail distribution.

Deference-type Approaches for Experience Ranking

The above considerations underscore the importance of coming up with a pleasure-pain scale that tries to take into account the non-linearity and non-normality of valence ratings. One idea we came up with was a “deference”-type approach, where we ask open-ended questions about people’s best and worst experiences and have them rank them against each other. Although locally the data would be very sparse, the idea was that there might be methods to integrate the collective patterns of deference into an approximate scale. If extended to populations of people who are known to have experienced extremes of valence, the approach would even allow us to unify the various pain scales (Scoville, Schmidt, KIP, etc.) and assign a kind of universal valence score to different categories of pain and pleasure.* That will be version 2.0. In the meantime, we thought to try to get a rough picture of the extreme joys and affections of members of the general public, which is what this article will focus on.

Normal World vs. Lognormal World

There is a world we could call the “Normal World”, where valence outliers are rare and most types of experiences affect people more or less similarly, distributed along a Gaussian curve. Then there is another, very different world we could call the “long-tailed world” or if we want to make it simple (acknowledging uncertainty) “Lognormal World”, where almost every valence distribution is a long-tail. So in the “Lognormal World”, say, for pleasure (and symmetrically for pain), we would expect to see a long-tail in the mean pleasure of experiences between different categories across all people, a long-tail in the amount of pleasure within a given type of experience across people, a long-tail for the number of times an individual has had a certain type of pleasure, a long-tail in the intensity of the pleasure experienced with a single category of experience within a single person, and so on. Do we live in the Normal World or the Lognormal World?

Predictions of Lognormal World

If we lived in the “Lognormal World”, we would expect:

  • That people will typically say that their top #1 best/worst experience is not only a bit better/worse than their #2 experience, but a lot better/worse. Like, perhaps, even multiple times better/worse.
  • That there will be a long-tail in the number of appearances of different categories (i.e. that a large amount, such as 80%, of top experiences will belong to the same narrow set of categories, and that there will be many different kinds of experiences capturing the remaining 20%).
  • That for most pairs of experiences x and y, people who have had both instances of x and y, will usually agree about which one is better/worse. We call such a relationship a “deference”. More so, we would expect to see that deference, in general, will be transitive (a > b and b > c implying that a > c).

To test the first and second prediction does not require a lot of data, but the third does because one needs to have enough comparisons to fill a lot of triads. The survey results we will discuss bellow are congruent with the first and second prediction. We did what we could with the data available to investigate the third, and tentatively, it seems to hold up (with ideas like deference network centrality analysis, triadic analysis, and tournament-style approaches).


Survey Setup

The survey asked the following questions: current level of pleasure, current level of pain, top 3 most pleasurable experiences (in decreasing order) along with pleasure ratings for each of them and the age when they were experienced, and the same for the top 3 most painful experiences. I specifically did not provide a set of broad categories (such as “physical” or “emotional”) or a drop-down menu of possible narrow categories (e.g. going to the movies, aerobic exercise, etc.). I wanted to see what people would say when the question was as open-ended as possible.

I also included questions aimed more directly at probing the long-tailed nature of valence: I asked participants to rate “how many times more pleasant was the #1 top experience relative to the #2 top experience” (and #2 relative to #3, and the same for the top most painful experiences).

I also asked them to describe in more detail the single most pleasant and unpleasant experiences, and added a box for comments at the end in order to see if anyone complained about the task (most people said “no comment”, many said they enjoyed the task, and one person said that it made them nostalgic). I also asked about basic demographics (age and gender). Participants earned $1.75 for the task, which seems reasonable given the time it took to complete in most cases.

Mechanical Turk: Participant Composition

The survey was run on Mechanical Turk. I requested “Masters” qualifications for 90/110 of the survey responses. To be a Mechanical Turk Master you need to have a good track record of task approval, which I reasoned would increase the rate of well thought-out high-quality responses (this turned out to be true). The participants’ genders were fairly balanced (50/97 women, 47/97 men), and the average age was 36.5 years (sd = 10):

age_distribution_no_bots

Age distribution

Bots (easy to spot – unless extremely sophisticated)

While reading the responses I discovered that some of them seemed to be generated by bots. Apparently task requesters started noticing the presence of bots a couple of years ago. This is obviously a problem for academics trying to use the service for their research, and for machine learning professionals using the service for data-tagging. Having been both of those things in the past, I can say that a few years ago I did not see any submissions that looked suspiciously bot-like. Though low-quality rushed responses did seem to be relatively common back then, I never observed bot-like responses to open-ended questions. Unfortunately this time I was able to spot several responses clearly written by bots. For example, one respondent answered the question “write a brief essay about your #1 best experience” with:

The reason these types of assignments are given so often is that anyone can write about their own experience and it doesn’t require any outside resources or research. However, even though anyone can tell a story about their life, that does not mean anyone can write a good essay about that experience. As a professor and teacher for 30 years, I’ve read thousands of essays and can tell you there is a distinct difference from telling a story about yourself and writing an excellent personal experience essay. The difference between good and great:

And it ends that way, with a colon indicating that the respondent is about to explain what the difference between good and great is. But it never does it. This answer, great, it is not.

In most cases the difference between a genuine response and a bot response was very obvious. That said, I erred on the side of caution for filtering bots and I got rid of answers even if they seemed just a little suspicious. This left me with 97 out of the 110 original responses. The following analysis was conducted on those 97 responses.

Preprocessing

Since the responses were open-ended I had to tag each of them with an experience category. To do this I read each response and identified the key theme in them and classified them with a label that was specific enough to distinguish it from nearby experiences (e.g. different types of fractures), but not so specific that we would never get more than one response per category (e.g. “breaking the middle finger in elementary school”). In general, most responses fell into very unambiguous categories (e.g. “When my father passed away” and “Watching my father die and take his last few breaths.” were both classified as “Father death”). About 10% of the responses were relatively ambiguous: it wasn’t clear what the source of the pain or pleasure was. To deal with those responses I used the label “Unspecified”. When some detail was present but ambiguity remained, such as when a broad type of pain or pleasure was mentioned but not the specific source I tagged it as “Unspecified X” where X was a broad category. For example, one person said that “broken bones” was the most painful experience they’ve had, which I labeled as “Unspecified fracture”.


Results

I should preface the following by saying that we are very aware of the lack of scientific rigor in this survey; it remains a pilot exploratory work. We didn’t specify the time-scale for the experiences (e.g. are we asking about the best minute of your life or the best month of your life?) or whether we were requesting instances of physical or psychological pain/pleasures. Despite this lack of constraints it was interesting to see very strong commonalities among people’s responses:

Appearance Base Rates

There were 77 and 124 categories of pleasure and pain identified, respectively. On the whole it seemed like there was a higher diversity of ways to suffer than of ways to experience intense bliss. Summoning the spirit of Tolstoy: “Happy families are all alike; every unhappy family is unhappy in its own way.”

Here are the raw counts for each category with at least two appearances:

pleasure_baserates_97_only_2andup_

Best experiences appearances (with at least two reports)

pain_baserates_97_only_2andup_

Worst experience appearances (with at least two reports)

For those who want to see the full list of number of appearances for each experience mentioned see the bottom of the article (I also clarify some of the more confusing labels there too)**.

A simple way to try to incorporate the information about the ranking is to weight experiences rated as top #1 with 3 points, those as top #2 with 2 points, and those as the top #3 with 1 point. If you do this, the experiences scores are:

pleasure_baserates_97_weighted_

Weighted appearances of best experiences (#1 – 3 points, #2 – 2 points, #3 – 1 point)

pain_baserates_97_weighted_

Weighted appearances of worst experiences (#1 – 3 points, #2 – 2 points, #3 – 1 point)

Average ratings

Given the relatively small sample size, I will only report the mean rating for pain and pleasure (out of 10) for categories of experience for which there were 6 or more respondents:

For pain:

  1. Father death (n = 19): mean 8.53, sd 2.3
  2. Childbirth (n = 16): mean 7.94, sd 2.16
  3. Grandmother death (n = 13): mean 8.12, sd 2.5
  4. Mother death (n = 11): mean 9.4, sd 0.62
  5. Car accident (n = 9): mean 8.42, sd 1.52
  6. Kidney stone (n = 9): mean 5.97, sd 3.17
  7. Migraine (n = 9): mean 5.36, sd 3.11
  8. Romantic breakup (n = 9): mean 7.11, sd 1.52
  9. Broken arm (n = 6): mean 8.28, sd 0.88
  10. Broken leg (n = 6): mean 7.33, sd 2.02
  11. Work failure (n = 6): mean 5.88, sd 3.57

(Note: the very high variance for kidney stones and migraine is partly explained by the presence of some very low responses, with values as low as 1.1/10 – perhaps misreported, or perhaps illustrating the extreme diversity of experiences of migraines and kidney stones).

And for pleasure:

  1. Falling in love (n = 42): mean 8.68, sd 1.74
  2. Children born (n = 41): mean 9.19, sd 1.64
  3. Marriage (n = 21): mean 8.7, sd 1.25
  4. Sex (n = 19): mean 8.72, sd 1.45
  5. College graduation (n = 13): mean 7.73, sd 1.4
  6. Orgasm (n = 11): mean 8.24, sd 1.63
  7. Alcohol (n = 8): mean 6.84, sd 1.59
  8. Vacation (n = 6): mean 9.12, sd 0.73
  9. Getting job (n = 6): mean 7.22, sd 1.47
  10. Personal favorite sports win (n = 6): mean 8.17, sd 1.23

Deference Graph of Top Experiences

We will now finally get to the more exploratory and fun/interesting analysis, at least in that it will generate a cool way of visualizing what causes people great joy and pain. Namely, the idea of using people’s rankings in order to populate a global scale across people and show it in the form of a graph of deferences. While the scientific literature has some studies that compare pain across different categories (e.g. 1, 2, 3) I was not able to find any dataset that included actual rankings across a variety of categories. Hence why it was so appealing to visualize this.

The simplest way of graphing experience deferences is to assign a node to each experience category and add an edge between experiences with deference relationships with a weight proportional to the number of directed deferences. For example, if 4 people have said that A was better than B, and 3 people have said that B was better than A, then there will be an edge from A to B with a weight of 4 and an edge from B to A with a weight of 3. Additionally, we can then run a graph centrality algorithm such as PageRank to see where the “deferences end up pooling”.

The images below do this: the PageRank of the graph is represented with the color gradient (darker shades of green/red representing higher PageRank values for good/bad experiences). In addition, the graphs also represent the number of appearances in the dataset for each category with the size of each node:

The main problem with the approach above is that it double (triple?) counts experiences that are very common. Say that, for example, taking 5-MeO-DMT produces a consistently higher-valence feeling relative to having sex. If we only have a couple of people who report both 5-MeO-DMT and sex as their top experiences, the edge from sex to 5-MeO-DMT will be very weak, and the PageRank algorithm will underestimate the value of 5-MeO-DMT.

In order to avoid the double counting effect of commonly-reported peak experiences we can instead add edge weights on the basis of the proportion with which an experience defers to the other. Let’s say that f(a, b) means “number of times that b is reported as higher than a”. Then the proportion would be f(a, b) / (f(a, b) + f(b, a)). Now, this introduces another problem, which is that pairs of experiences that appear together very infrequently might get a very high proportion score due to a low sample size. In order to prevent this we use Laplace smoothing and modify the equation to (f(a, b) + 1) / (f(a, b) + f(b, a) + 2). Finally, we transform this proportion score from the range of 0 to 1 to the range of -1 to 1 by multiplying by 2 and subtracting one. We call this a “rebalanced smoothed proportion” w(a, b):

CodeCogsEqn

Rebalanced smoothed proportion

I should note that this is not based on any rigorous math. The equation is based on my intuition for what I would expect to see in such a graph, namely a sort of confidence-weighted strength of directionality, but I do not guarantee that this is a principled way of doing so (did I mention this is a pilot small-scale low-budget ‘to a first approximation’ study?). I think that, nonetheless, doing this is still an improvement upon merely using the raw deference counts as the edge weights. To visualize what w(a, b) looks like I graphed its values for a and b in the range of 0 to 20 (literally typing the equation into the google search bar):

To populate the graph I only use the positive edge weights so that we can run the PageRank algorithm on it. This now looks a lot more reasonable and informative as a deference graph than the previous attempts:

pleasure_97_balanced_2

Best experiences deference graph: Edge weights based on the rebalanced smoothed proportions, size of nodes is proportional to number of appearances in the dataset, and the color tracks the PageRank of the graph. Edge color based on source node.

 

pain_network_97_balanced

Worst experiences deference graph: Edge weights based on the rebalanced smoothed proportions, size of nodes is proportional to number of appearances in the dataset, and the color tracks the PageRank of the graph. Edge color based on source node.

By taking the PageRank of these graphs (calculated with NetworkX) we arrive at the following global rankings:

pleasure_pagerank_97_

PageRank of the graph of best experiences with edge weights computed with the rebalanced smoothed proportion equation

pain_pagerank_97__

PageRank of the graph of worst experiences with edge weights computed with the rebalanced smoothed proportion equation

Intuitively this ranking seems more aligned with what I’ve heard before, but I will withhold judgement on it until we have much more data.

Triadic Analysis

With a more populated deference graph we can analyze in detail the degree to which triads (i.e. sets of three experiences such that each of the three possible deferences are present in the graph) show transitivity (cf. Balance vs. Status Theory).

In particular, we should compare the prevalence of these two triads:

triad_analysis

Left: 030T, Right: 030C (source)

The triads above are 030T, which is transitive, and 030C, which is a loop. The higher the degree of agreement between people and the higher the probability of the existence of an underlying shared scale, we would expect to see more triads of the type 030T relative to 030C. That said, a simple ratio is not enough, since the expected proportion between these two triads can be an artifact of the way the graph is constructed and/or its general shape (and hence the importance of comparing against randomized graphs that preserve as many other statistical features as possible). With our graph, we noticed that the very way in which the edges were introduced generated an artifact of a very strong difference between these two types of triads:

In the case of pain there are 105 ‘030T’, and 3 ‘030C’. And for the pleasure questions there were 98 ‘030T’, and 9 ‘030C’. That said, many of these triads are the artifact of taking into account the top three experiences, which already generates a transitive triad by default when n = 1 for that particular triad of experiences. To avoid this artifact, we filtered the graph by only adding edges when a pair of experiences appeared at least twice (and discounting the edges where w(a, b) = 0). With this adjustment we got 2 ‘030T’, and 1 ‘030C’ for the pain questions, and 1 ‘030T’, and 0 ‘030C’ for the pleasure question. Clearly there is not enough data to meaningfully conduct this type of analysis. If we extend the study and get a larger sample size, this analysis might be much more informative.

Latent Trait Ratings

A final approach I tried for deriving a global ranking of experiences was to assume a latent parameter for pain or pleasure of different experiences and treating the rankings as the tournament results of participants with skill equal to this latent trait. So when someone says that an experience of sex was better than an experience of getting a new bike we imagine that “sex” had a match with “getting bike” and that “sex” won that match. If we do this, then we can import any of the many tournament algorithms that exist (such as the Elo rating system) in order to approximate the latent “skill” trait of each experience (except that here it is the “skill” to cause you pleasure or pain, rather than any kind of gaming ability).

Interestingly, this strategy has also been used in other areas outside of actual tournaments, such as deriving university rankings based on the choices made by students admitted to more than one college (see: Revealed Preference Rankings of US Colleges and Universities).

I should mention that the fact that we are asking about peak experiences likely violates some of the assumptions of these algorithms, since the fact that a match takes place is already information that both experiences made it into the top 3. That said, if the patterns of deference are very strong, this might not represent a problem.

To come up with this tournament-style ranking I decided to go for a state-of-the-art algorithm. The one that I was able to find and use was Microsoft Research’s algorithm called TrueSkill (which is employed to rank players in Xbox LIVE). According to their documentation, to arrive at a conservative “leaderboard” that balances the estimated “true skill” and the uncertainty around it, they recommend ranking by the expected skill level minus three times the standard error around this estimate. If we do this, we arrive at the following experience “leaderboards”:

pleasure_97_trueskill_conservative

Conservative TrueSkill scores for best experiences (mu – 3*sigma)

pain_97_trueskill_conservative

Conservative TrueSkill scores for worst experiences (mu – 3*sigma)

Long-tails in Responses to “How Many Times Better/Worse” Question

The survey included four questions aimed at comparing the relative hedonic values of peak experiences: “Relative to the 1st most pleasant experience, how many times better was the 2nd most pleasant experience?” (This was one, the other three were the permutations of also asking about 2nd vs. 3rd and about the bad experiences):

(Note: I’ll ignore the responses to the comparison between the 2nd and 3rd worst pains because I messed up the question -I forgot to substitute “better” for “worse”).

I would understand the skepticism about these graphs. But at the same time, I don’t think it is absurd that for many people the worst experience they’ve had is indeed 10 or 100 times worse than the second worst. For example, someone who has endured a bad Cluster Headache will generally say that the pain of it is tens or hundreds of times worse than any other kind of pain they have had (say, breaking a bone or having skin burns).

The above distributions suggest a long-tail for the hedonic quality of experiences: say that the hedonic quality of each day is distributed along a log-normal distribution. A 45 year old has experienced roughly 17,000 days. Let’s say that such a person’s experience of pain each day is sampled from a log-normal distribution with a Gaussian exponent with a mean of 10 and a standard deviation of 5. If we take 100 such people, and for each of them we take the single worst and the second worst days of their lives, and then take the ratio between them, we will have a distribution like this (simulated in R):

If you smooth the empirical curves above you would get a distribution that looks like these simulations. You really need a long-tail to be able to get results like “for 25% of the participants the single worst experience was at least 4 times as bad as the 2nd worst experience.” Compare that to the sort of pattern that you get if the distribution was normal rather than log-normal:

As you can see (zooming in on the y-axis), the ratios simply do not reach very high values. With the normal distribution simulated here, we see that the highest ratio we achieve is around 1.3, as opposed to the empirical ratios of 10+.*** If you are inclined to believe the survey responses- or at least assign some level of credibility to the responses in the 90th-percentile and below-, the data is much more consistent with a long-tail distribution for hedonic values relative to a normal distribution.

Discussion

Key Pleasures Surfaced

Birth of children

I have heard a number of mothers and father say that having kids was the best thing that ever happened to them. The survey showed this was a very strong pattern, especially among women. In particular, a lot of the reports deal with the very moment in which they held their first baby in their arms for the first time. Some quotes to illustrate this pattern:

The best experience of my life was when my first child was born. I was unsure how I would feel or what to expect, but the moment I first heard her cry I fell in love with her instantly. I felt like suddenly there was another person in this world that I cared about and loved more than myself. I felt a sudden urge to protect her from all the bad in the world. When I first saw her face it was the most beautiful thing I had ever seen. It is almost an indescribable feeling. I felt like I understood the purpose and meaning of life at that moment. I didn’t know it was possible to feel the way I felt when I saw her. I was the happiest I have ever been in my entire life. That moment is something that I will cherish forever. The only other time I have ever felt that way was with the subsequent births of my other two children. It was almost a euphoric feeling. It was an intense calm and contentment.

—————

I was young and had a difficult pregnancy with my first born. I was scared because they had to do an emergency c-section because her health and mine were at risk. I had anticipated and thought about how the moment would be when I finally got to hold my first child and realize that I was a mother. It was unbelievably emotional and I don’t think anything in the world could top the amount of pleasure and joy I had when I got to see and hold her for the first time.

—————

I was 29 when my son was born. It was amazing. I never thought I would be a father. Watching him come into the world was easily the best day of my life. I did not realize that I could love someone or something so much. It was at about 3am in the morning so I was really tired. But it was wonderful nonetheless.

—————

I absolutely loved when my child was born. It was a wave of emotions that I haven’t felt by anything before. It was exciting and scary and beautiful all in one.

No luck for anti-natalists… the super-strong drug-like effects of having children will presumably continue to motivate most humans to reproduce no matter how strong the ethical case against doing so may be. Coming soon: a drug that makes you feel like “you just had 10,000 children”.

Falling in Love

The category of “falling in love” was also a very common top experience. I should note that the experiences reported were not merely those of “having a crush”, but rather, they typically involved unusually fortunate circumstances. For instance, a woman reported being friends with her crush for 7 years. She thought that he was not interested in her, and so she never dared to confess her love for him… until one day, out of the blue, he confessed his love for her. Other experiences of falling in involve chance encounters with childhood friends that led to movie-deserving romantic escapades, forbidden love situations, and cases where the person was convinced the lover was out of his or her league.

Travel/Vacation

The terms “travel” and “vacation” may sound relatively frivolous in light of some of the other pleasures listed. That said, these were not just any kind of travel or vacation. The experiences described do seem rather extraordinary and life-changing. For example, talking about back-packing alone in France for a month, biking across the US with your best friend, or a long trip in South East Asia with your sibling that goes much better than planned.

MDMA/LSD/Psilocybin

It is significant that out of 97 people four of them listed MDMA as one of the most pleasant experiences of their lives. This is salient given the relatively low base rate of usage of this drug (some surveys saying about 12%, which is probably not too far off from the base rate for Mechanical Turk workers using MDMA). This means that a high percentage of people who have tried MDMA will rate it as as one of their top experiences, thus implying that this drug produces experiences sampled from an absurdly long-tailed high-valence distribution. This underscores the civilizational significance of inventing a method to experience MDMA-like states of consciousness in a sustainable fashion (cf. Cooling It Down To Partying It Up).

Likewise, the appearance of LSD and psilocybin is significant for the same reason. That said, measures of the significance of psychedelic experiences in psychedelic studies have shown that a high percentage of those who experience such states rate them among their top most meaningful experiences.

About-two-thirds-of-participants-who-received-psilocybin-reported-a-mystical-experience

Games of Chance Earnings

Four participants mentioned earnings in games of chance. These cases involved earning amounts ranging from $2,000 all the way to a truck (which was immediately sold for money). What I find significant about this is that these experiences are at times ranked above “college graduation” and other classically meaningful life moments. This brings about a crazy utilitarian idea: if indeed education is as useless as many people in the intellectual elite are saying these days (ex. The Case Against Education) we might as well stop subsidizing higher education and instead make people participate in opt-out games of chance rigged in their favor. Substitute the Department of Education for a Department of Lucky Moments and give people meaningful life experiences at a fraction of the cost.

Key Pains Surfaced

Kidney Stones and Migraines

The fact that these two medical issues were surfaced is, I think, extremely significant. This is because the lifetime incidence of kidney stones is about 10% (~13% for men, 7% for women) and for migraines it is around 13% (9% for men, 18% for women). In the survey we saw 9/93 people mentioning kidney stones, and the same number of people mentioning migraines. In other words, there is reason to believe that a large fraction of the people who have had either of these conditions will rate them as one of their top 3 most painful experiences. This fact alone underscores the massive utilitarian benefit that would come from being able to reduce the incidence of these two medical problems (luckily, we have some good research leads for addressing these problems at a large scale and in a cost-effective way: DMT for migraines, and frequency specific microcurrent for kidney stones)

Childbirth

Childbirth was mentioned 16 times, meaning that roughly 30% of women rate it as one of their three most painful experiences. While many people may look at this and simply nod their heads while saying “well, that’s just life”, here at Qualia Computing we do not condone that kind of defeatism and despicable lack of compassion. As it turns out, there are fascinating research leads to address the pain of childbirth. In particular, Jo Cameron, a 70 year old vegan schoolteacher, described her childbirth by saying that it “felt like a tickle”. She happens to have a mutation in the FAAH gene, which is usually in charge of breaking down anandamine (a neurotransmitter implicated in pain sensitivity and hedonic tone). As we’ve argued before, every child is a complete genetic experiment. In the future, we may as well try to at least make educated guesses about our children’s genes associated with low mood, anxiety, and pain sensitivity. In defiance of common sense (and the Bible) the future of childbirth could indeed be one devoid of intense pain.

Car accidents

Car accidents are extremely common (the base rate is so high that by the age of 40 or so we can almost assume that most people have been in at least one car accident, possibly multiple). More so, it seems likely that the health-damaging effects of car accidents, by their nature, follow a long-tail distribution. The high base rate of people mentioning car accidents in their top 3 most painful experiences underscores the importance of streamlining the process of transitioning into the era of self-driving cars.

Death of Father and Mother

This one does not come as a surprise, but what may stand out is the relatively higher frequency of mentions of “death of father” relative to “death of mother”. I think this is an artifact of the longevity difference between men and women. This is in agreement with the observed effect of age: about 15% vs. 25% of people under and over 40 had mentioned the death of their father, as opposed to a difference of 5% vs. 25% for death of mother. The reason why the father might be over-represented might simply be due to the lower life expectancy of men relative to women, and hence the father, on average, dying earlier. Thus, it being reported more frequently by a younger population.

Future Directions for Methodological Approaches:

Graphical Models with Log-normal Priors

After trying so many analytic angles on this dataset, what else is there to do? I think that as a proof of concept the analysis presented here is pretty well-rounded. If the Qualia Research Institute does well in the funding department, we can expect to extend this pilot study into a more comprehensive analysis of the pleasure-pain axis both in the general population and among populations who we know have endured or enjoyed extremes of valence (such as cluster headache sufferers or people who have tried 5-MeO-DMT).

In terms of statistical models, an adequate amount of data would enable us to start using probabilistic graphical models to determine the most likely long-tail distributions for all of the key parameters of pleasure and pain. For instance, we might want to develop a model similar to Item Response Theory where:

  1. Each participant samples experiences from a distribution.
  2. Each experience category generates samples with an empirically-determined base rate probability (e.g. chances that it happens in a given year), along with a latent hedonic value distribution.
  3. A “discrimination function” f(a, b) that gives the probability that experience of hedonic value a is rated as more pleasant (or painful) relative an experience with a hedonic value of b.
  4. And a generative model that estimates the likelihood of observing experiences as the top 3 (or top x) based on the parameters provided.

In brief, with an approach like the above we can potentially test the model fit for different distribution types of hedonic values per experience. In particular, we would be able to determine if the model fit is better if the experiences are drawn from a Gaussian vs. a log-normal (or other long-tailed) distribution.

Finally, it might be fruitful to explicitly ask about whether participants have had certain experiences in order to calibrate their ratings, or even have them try a battery of standardized pain/pleasure-inducing stimuli (capsaicin extract, electroshocks, stings, massage, orgasm, etc.). We could also find the way to combine (a) the numerical ratings, (2) the ranking information, and (3) the “how many times better/worse” responses into a single model. And for best results, restrict the analysis to very recent experiences in order to reduce recall biases.

Closing Thoughts on the Valence Scale

To summarize, I believe that the case for a long-tail account of the pleasure-pain axis is very defensible. This picture is supported by:

  1. The long-tailed nature of neuronal cascades,
  2. The phenomenological accounts of intense pleasure and pain (w/ phenomenological accounts of time and space expansion),
  3. The way in which pain scales are constructed by those who developed them, and
  4. The analytic results of the pilot study we conducted and presented here.

In turn, these results give rise to a new interpretation of psychophysical observations such as Weber’s Law. Namely, that Just Noticeable Differences may correspond to geometric differences in qualia, not only in sensory stimuli. That is, that the exponential nature of many cases where Weber’s Law appears are not merely the result of a logarithmic compression on the patterns of stimulation at the “surface” of our sense organs. Rather, the observations presented here suggest that these long-tails deal directly with the quality and intensity of conscious experience itself.


Additional Material

Dimensionality of Pleasure and Pain

Pain and pleasure may have an intrinsic “dimensionality”. Without elaborating, we will merely state that a generative definition for the “dimensionality of an experience” is the highest “virtual dimension” implied by the patterns of correlation between degrees of freedom. The hot pepper hands account I related suggested a kind of dimensional phase transition between 4/10 and 5/10 pain, where the patterns of a certain type (4/10 “sparks” of pain) would sometimes synchronize and generate a new type of higher-dimensional sensation (5/10 “solitons” of pain). To illustrate this idea further:

First, in Hot Ones, Kumail Nanjiani describes several “leaps” in the spiciness of the wings, first at around 30,000 Scoville (“this new ghost that appears and only here starts to visit you”), and second at around 130k Scoville (paraphrasing: “like how NES to Super Nintendo felt like a big jump, but then Super Nintendo to N64 was an even bigger leap” – “Now we are playing in the big leagues motherfucker! This is fucking real!”). This hints at a change in dimensionality, too.

And second, Shinzen Young‘s advice about dealing with pain involves not resisting it. He discusses how suffering is generated by the coordination between emotional, cognitive, and physical mental formations. If you can keep each of these mental formations happening independently and don’t allow their coordinated forms, you will avoid some of what makes the experience bad. This also suggests that higher-dimensional pain is qualitatively worse. Pragmatically, training to do this may make sense for the time being, since we are still some years away from sustainable pain-relief for everyone.

Mixed States

We have yet to discuss in detail how mixed states come into play for a log-normal valence scale. The Symmetry Theory of Valence would suggest that most states are neutral in nature and that only processes that reduce entropy locally such as neural annealing would produce highly-valenced states. In particular, we would see that high-valence states have very negative valence states nearby in configuration space; if you take a very good high-energy state and distort it in a random direction it will likely feel very unpleasant. The points in between would be mixed valence, which account for the majority of experiences in the wild.

Qualia Formalism

Qualia Formalism posits that for any given system that sustains experiences, there is a mathematical object such that the mathematical features of that object are isomorphic to the system’s phenomenology. In turn, Valence Structuralism posits that the hedonic nature of experience is encoded in a mathematical feature of this object. It is easier to find something real if you posit that it exists (rather than try to explain it away). We have suggested in the past that valence can be explained in terms of the mathematical property of symmetry, which cashes out in the form of neural dissonance and consonance.

In contrast to eliminativist, illusionist, and non-formal approaches to consciousness, at QRI we simply start by assuming that experience has a deep ground truth structure and we see where we can go from there. Although we currently lack the conceptual schemes, science, and vocabulary needed to talk in precise terms about different degrees of pleasure and pain (though we are trying!), that is not a good reason to dismiss the first-person claims and indirect pieces of evidence concerning the true amounts of various kinds of qualia bound in each moment of experience. If valence does turn out to intrinsically be a mathematical feature of our experience, then both its quality and quantity could very well be precisely measurable, conceptually crisp, and tractable. A scientific fact that, if proven, would certainly have important implications in ethics and meta-ethics.


Notes:

* It’s a shame that Coyote Peterson didn’t rate the pain produced by the various wings he ate on the Hot Ones show relative to insect stings, but that sort of data would be very helpful in establishing a universal valence scale. More generally, stunt-man personalities like the L.A. Beast who subject themselves to extremes of negative valence for Internet points might be an untapped gold mine for experience deference data (e.g. How does eating the most bitter substance known compare with the bullet ant glove? Asking this guy might be the only way to find out, without creating more casualties).

**Base rate of mentions of worst experiences:

[('Father death', 19), ('Childbirth', 16), ('Grandmother death', 13), ('Mother death', 11), ('Car accident', 9), ('Kidney stone', 9), ('Migraine', 9), ('Romantic breakup', 9), ('Broken arm', 6), ('Broken leg', 6), ('Work failure', 6), ('Divorce', 5), ('Pet death', 5), ('Broken foot', 4), ('Broken ankle', 4), ('Broken hand', 4), ('Unspecified', 4), ('Friend death', 4), ('Sister death', 4), ('Skin burns', 3), ('Skin cut needing stitches', 3), ('Financial ruin', 3), ('Property loss', 3), ('Sprained ankle', 3), ('Gallstones', 3), ('Family breakup', 3), ('Divorce of parents', 3), ('C-section recovery', 3), ('Love failure', 2), ('Broken finger', 2), ('Unspecified fracture', 2), ('Broken ribs', 2), ('Unspecified family death', 2), ('Broken collarbone', 2), ('Grandfather death', 2), ('Unspecified illness', 2), ('Period pain', 2), ('Being cheated', 2), ('Financial loss', 2), ('Broken tooth', 2), ('Cousin death', 2), ('Relative with cancer', 2), ('Cluster headache', 2), ('Unspecified leg problem', 2), ('Root canal', 2), ('Back pain', 2), ('Broken nose', 2), ('Aunt death', 2), ('Wisdom teeth', 2), ('Cancer (eye)', 1), ('Appendix operation', 1), ('Dislocated elbow', 1), ('Concussion', 1), ('Mono', 1), ('Sexual assault', 1), ('Kidney infection', 1), ('Hemorrhoids', 1), ('Tattoo', 1), ('Unspecified kidney problem', 1), ('Unspecified lung problem', 1), ('Unspecified cancer', 1), ('Unspecified childhood sickness', 1), ('Broken jaw', 1), ('Broken elbow', 1), ('Thrown out back', 1), ('Lost sentimental item', 1), ('Abortion', 1), ('Ruptured kidney', 1), ('Big fall', 1), ('Torn knee', 1), ('Finger hit by hammer', 1), ('Injured thumb', 1), ('Brother in law death', 1), ('Knocked teeth', 1), ('Unspecified death', 1), ('Ripping off fingernail', 1), ('Personal anger', 1), ('Wrist pain', 1), ('Getting the wind knocked out', 1), ('Blown knee', 1), ('Burst appendix', 1), ('Tooth abscess', 1), ('Tendinitis', 1), ('Altruistic frustration', 1), ('Leg operation', 1), ('Gallbladder infection', 1), ('Broken wrist', 1), ('Stomach flu', 1), ('Running away from family', 1), ('Child beating', 1), ('Sinus infection', 1), ('Broken thumb', 1), ('Family abuse', 1), ('Miscarriage', 1), ('Tooth extraction', 1), ('Feeling like your soul is lost', 1), ('Homelessness', 1), ('Losing your religion', 1), ('Losing bike', 1), ('Family member in prison', 1), ('Crohn s disease', 1), ('Irritable bowel syndrome', 1), ('Family injured', 1), ('Unspecified chronic disease', 1), ('Fibromyalgia', 1), ('Blood clot in toe', 1), ('Infected c-section', 1), ('Suicide of lover', 1), ('Dental extraction', 1), ('Unspecified partner abuse', 1), ('Infertility', 1), ('Father in law death', 1), ('Broken neck', 1), ('Scratched cornea', 1), ('Swollen lymph nodes', 1), ('Sun burns', 1), ('Tooth ache', 1), ('Lost custody of children', 1), ('Unspecified accident', 1), ('Bike accident', 1), ('Broken hip', 1), ('Not being loved by partner', 1), ('Dog bite', 1), ('Broken skull', 1)]

Base rate of mentions of best experiences:

[('Falling in love', 42), ('Children born', 41), ('Marriage', 21), ('Sex', 19), ('College graduation', 13), ('Orgasm', 11), ('Alcohol', 8), ('Vacation', 6), ('Getting job', 6), ('Personal favorite sports win', 6), ('Nature scene', 5), ('Owning home', 5), ('Sports win', 4), ('Graduating highschool', 4), ('MDMA', 4), ('Getting paid for the first time', 4), ('Amusement park', 4), ('Game of chance earning', 4), ('Job achievement', 4), ('Getting engaged', 4), ('Cannabis', 3), ('Eating favorite food', 3), ('Unexpected gift', 3), ('Moving to a better location', 3), ('Travel', 3), ('Divorce', 2), ('Gifting car', 2), ('Giving to charity', 2), ('LSD', 2), ('Won contest', 2), ('Friend reunion', 2), ('Winning bike', 2), ('Kiss', 2), ('Pet ownership', 2), ('Children', 1), ('First air trip', 1), ('First kiss', 1), ('Public performance', 1), ('Hugs', 1), ('Unspecified', 1), ('Recovering from unspecified kidney problem', 1), ('College party', 1), ('Graduate school start', 1), ('Financial success', 1), ('Dinner with loved one', 1), ('Feeling supported', 1), ('Children graduates from college', 1), ('Family event', 1), ('Participating in TV show', 1), ('Psychedelic mushrooms', 1), ('Opiates', 1), ('Having own place', 1), ('Making music', 1), ('Becoming engaged', 1), ('Theater', 1), ('Extreme sport', 1), ('Armed forces graduation', 1), ('Birthday', 1), ('Positive pregnancy test', 1), ('Feeling that God exists', 1), ('Belief that Hell does not exist', 1), ('Getting car', 1), ('Academic achievement', 1), ('Helping others', 1), ('Meeting soulmate', 1), ('Daughter back home', 1), ('Winning custody of children', 1), ('Friend stops drinking', 1), ('Masturbation', 1), ('Friend not dead after all', 1), ('Child learns to walk', 1), ('Attending wedding of loved one', 1), ('Children safe after dangerous situation', 1), ('Unspecified good news', 1), ('Met personal idol', 1), ('Child learns to talk', 1), ('Children good at school', 1)]

For clarity – “Personal favorite sports win” means that the respondent was a participant in the sport as opposed to a spectator (which was labeled as “Sports win”). The difference between “Sex” and “Orgasm” is that Sex refers to the entire act including foreplay and cuddles whereas Orgasm refers to the specific moment of climax. For some reason people would either mention one or the other, and emphasize very different aspects of the experience (e.g. intimacy vs. physical sensation) so I decided to label them differently.

*** It is possible that some fine-tuning of parameters could give rise to long-tail ratios even with a normal distribution (especially if the mean is, say, a negative value and the standard deviation is very wide). But in the general case a normal distribution will have a fairly narrow range for the ratios of the “top value divided by the second top value”. So at least as a general qualitative argument, I think, the simulations do suggest a long-tailed nature for the reported hedonic values.

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

Triple S Genetic Counseling: Predicting Hedonic-Set Point with Commercial-Grade DNA Testing as an Effective Altruist Project

The term “Transhumanism” has many senses. It is a social movement, a philosophy, a set of technologies, and a conceptual rallying flag. David Pearce pins down the core sentiment behind the term like this:

If we get things right, the future of life in the universe can be wonderful beyond the bounds of human imagination: a “triple S” civilisation of superlongevity, superintelligence and superhappiness.

– David Pearce, in The 3 Supers

The concept of a “triple S” civilization is very widely applicable. For example, one can imagine future smart homes designed with it in mind. Such smart homes would have features to increase your longevity (HEPA filters, humidity control, mold detectors, etc.), increase your intelligence (adaptive noise-canceling, optimal lighting, smart foods), and happiness (mood-congruent lighting, music, aromas, etc.). Since there are trade-offs between these dimensions, one could specify how much one values each of them in advance, and the smart home would be tasked with maximizing a utility function based on a weighted average between the three S’s.

Likewise, one could apply the “triple S” concept to medical care, lifestyle choices, career development, governance, education, etc. In particular, one could argue that a key driver for the realization of a triple S civilization would be what I’d like to call “triple S genetic counseling.” In brief, this is counseling for prospective parents in order to minimize the risks of harming one’s children by being oblivious to the possible genetic risk for having a reduced longevity, intelligence, or happiness. Likewise, in the more forward-looking transhumanist side of the equation, triple S genetic counseling would allow parents to load the genetic dice in their kid’s favor in order to make them as happy, long-lived, and smart as possible.

Genetic counseling, as an industry, is indeed about to explode (cf. Nature’s recent article: Prospective parents should be prepared for a surge in genetic data). Predictably, there will be a significant fraction of society that will question the ethics of e.g. preimplantation genetic diagnosis for psychological traits. In practice, parents who are able to afford it will power ahead, for few prospective parents truly don’t care about the (probabilistic) well-being of their future offspring. My personal worry is not so much that this won’t happen, but that the emphasis will be narrow and misguided. In particular, both predicting health and intelligence based on sequenced genomes are very active areas of research. I worry that happiness will be (relatively) neglected. Hence the importance of emphasizing all three S’s.

In truth, I think that predicting the hedonic set-point of one’s potential future kids (i.e. the average level of genetically-determined happiness) is a relatively more important project than predicting IQ (cf. A genome-wide association study for extremely high intelligenceBGI). In addition, I anticipate that genetic-based models that predict a person’s hedonic set-point will be much more accurate than those that predict IQ. As it turns out, IQ is extremely polygenetic, with predictors diffused across the entire genome, and it is a very evolutionary recent axis of variance across the population. Predictors of hedonic-set point (such as the “pain-knob gene” SCN9A and it’s variants), on the other hand, are ancient and evolutionarily preserved across the phylogenetic tree. This makes baseline happiness a likely candidate for having a straight-forward universal physiological implementation throughout the human population. Hence my prediction that polygenetic scores of hedonic-set point will be much more precise than those for IQ (or even longevity).

Given all of the above, I would posit that a great place to start would be to develop a model that predicts hedonic set-point using all of the relevant SNPs offered by 23andMe*.  Not only would this be “low-hanging fruit” in the field of genetic counseling, it may also be a project that is way up there, close to the top of the “to do” list in Effective Altruism (cf. Cause X; Google Hedonics).

I thought about this because I saw that 23andMe reports on health predispositions based on single SNPs. From a utilitarian point of view, of particular interest are SNPs related to the SCN9A gene. For example, I found that 23andMe has the rs6746030 SNP, which some studies show can account for a percentage of the variance associated with pain in Parkinson’s and other degenerative diseases. The allele combination A/A is bad, making you more prone to experience pain intensely. This is just one SNP, though, and there ought to be a lot of other relevant SNPs, not only of the SCN9A gene but elsewhere too (e.g. involved in MAO enzymes, neuroplasticity, and pleasure centers innervation).

Concretely, the task would involve making two models and then combining them:

The first model uses people’s responses to 23andMe surveys to come up with a good estimate of a person’s hedonic set-point. Looking at some of the questions they ask, I would argue that there are more than enough dimensions to model how people vary in their hedonic set-point. They ask about things such as perception of pain, perception of spiciness, difficulty sleeping, stress levels, whether exercise is pleasant, etc. From a data science point of view, the challenge here is that number of responses provided by each participant is very variable; some power users respond to every question (and there are hundreds and hundreds), while most people respond to a few questions only, and a substantial minority respond to no questions at all. Most likely, the distribution of responses per participant follows a power law. So the model to build here has to be resilient against absent data. This is not an insurmountable problem, though, considering the existence of Bayesian Networks, PGMs, and statistical paradigms like Item Response Theory. For this reason, the model would need to both predict the most likely hedonic set-point of each participant, and provide confidence intervals specific to the participant based on the quality and relevance of the questions answered.

The second model would involve clustering and dimensionality reduction applied to the SNPs that are likely to be relevant for hedonic set-point. For example, one dimension would likely be a cluster of SNPs that are associated with “maximum intensity of pain”, another might be “how quickly pain subsides once it’s stimulated”, another “how much does pleasure counter-balance pain”, and so on. Each of these dimensions is likely to be determined by different neural circuits, and interact in non-linear ways, so they deserve their own separate dimension.

And finally, one would make a third model that combines the two models above, which predicts the hedonic set-point of a person derived from the first model using the genetic dimensions found by the second model. If you are an up-and-coming geneticist, I would like to nudge you in the direction of looking into this. As a side effect, you might as well get filthy rich in the process, as the genetic counseling field explodes in the next decade.


Bonus Content: What About Us?

Admittedly, many people will note that predicting a fraction of the variance of people’s hedonic set point with commercial DNA testing products will only really alleviate suffering in the medium to long term. The people who will benefit from this technology haven’t been born yet. In the meantime, what do we do about the people who currently have low hedonic set-points? Here is a creative, politically incorrect, and enticing idea:

Let’s predict which recreational drugs have the best cost-benefit profile for individuals based on their genetic makeup.

It is no secret that people react differently to drugs. 23andMe, among others, is currently doing research to predict your particular reaction to a drug based on your genetic makeup (cf. 23andMe can now tell you how you’ll react to 50+ common drugs). Unfortunately for people with anxiety, depression, chronic pain, and other hedonic tone illnesses, most psychiatric drugs are rather subtle and relatively ineffective. No wonder, compared to heroin, an SSRI is not likely to make you feel particularly great. As David Pearce argued in his essay Future Opioids, there is substantial evidence that many people who become addicts are driven to take recreational substances due to the fact that their endogenous opioid system is dysfunctional (e.g. they may have bad variants of opioid receptors, too many endorphin-degrading enzymes, etc.). The problem with giving people hard drugs is not that they don’t work in the short term; it is that they tend to backfire in the long-term and have cumulative negative health effects. As an aside, from the pharmaceutical angle, my main interest is the development of Anti-tolerance Drugs, which would allow hard drugs to work as mood-enhancers indefinitely.

This is not to say that there aren’t lucky people for whom the cost-benefit ratio of taking hard drugs is, in fact, rather beneficial. In what admittedly must have been a tongue-in-cheek marketing move, in the year 2010 the genetic interpretation company Knome (now part of Tute Genomics) studied Ozzy Osbourne‘s entire genome in order to determine how on earth he has been able to stay alive despite the gobs and gobs of drugs he’s taken throughout his life. Ozzy himself:

“I was curious, [g]iven the swimming pools of booze I’ve guzzled over the years—not to mention all of the cocaine, morphine, sleeping pills, cough syrup, LSD, Rohypnol…you name it—there’s really no plausible medical reason why I should still be alive. Maybe my DNA could say why.”

Ozzy Osbourne’s Genome (Scientific American, 2010)

Tentatively, Knome scientists said, Ozzy’s capacity to drink entire bottles of Whisky and Gin combined with bowlfuls of cocaine and multiple packs of cigarettes over the course of… breakfast… without ending up in the hospital may be due to novel mutations in his alcohol dehydrogenase gene (ADH4), as well as, potentially, the gene that codes for CLTCL1, a protein responsible for the intake of extra-cellular material into the cell’s inside. These are wild speculations, to be clear, but the general idea is brilliant.

Indeed, not everyone reacts in the same way to recreational drugs. A recent massive study on the health effects of alcohol funded by the Bill and Melinda Gates Foundation (cf. No amount of alcohol is good for your overall health) suggests that alcohol is bad for one’s health at every dosage. This goes against the common wisdom backed up with numerous studies that light-drinkers (~1 alcohol unit a day) live longer and healthier lives than teetotalers. The new study suggests that this is not a causal effect of alcohol. Rather, it so happens that a large fraction of teetotalers are precisely the kind of people who react very badly to alcohol as a matter of poor metabolism. Hence, teetotalers are not unhealthy because they avoid alcohol; they avoid alcohol because they are unhealthy, which explains their shorter life expectancy on average. That said, the study did show that 1 alcohol unit a day is, although damaging, very minimally so:

Anyhow, the world’s cultural fascination with alcohol is bizarre to me, considering the existence of drugs that have a much better hedonic and cost-benefit profile (cf. State-Space of Drug Effects). Perhaps finding out with genetic testing that you are likely to be an above-average alcohol metabolizer might be good to lessen your worry about having a couple of drinks now and then. But the much bigger opportunity here would be to allow you to find drugs that you are particularly compatible with. For example, a genetic test might determine based on a polygenetic score that you might benefit a whole lot from taking small amounts of e.g. Khat  (or some such obscure and relatively benign euphoriant). That is, that your genetic make-up is such that Khat will be motivation enhancing, empathy-increasing, good for your heart and lungs, reduce the rate of dopamine neuron death, etc. while at the same time producing little to no hangovers, no irritability, no sleep issues, or social dysfunction. Even though you may have thought that you are “not an uppers person”, perhaps that’s because, genetically, every other upper you have ever tried is objectively terrible for your health. But Khat wouldn’t be. Wouldn’t this information be useful? Indeed, I would posit, this might be a great step in the right direction in order to achieve the goal of  Wireheading Done Right.


*23andMe is here used as a shorthand for services in general like this (including Ancestry, Counsyl, Natera, etc.)

Featured image credit: source.

Lucid LSD Trip Report from an Anonymous Reader

Writer: Anonymous (here substituted as “Bill”)

Dose: 2 blotters

I remember at one point feeling and saying that I was on the “sandy beaches of time.” Normally there are story arcs to events. There’s peak arousal and closure. But the hoffman [“LSD blotter”] was sustained arousal. In an expected upbeat I found a downbeat. All downbeats. So I found myself with extra moments unexpectedly. Moments that normally would have been blank or dim transitions were just as full as the moments they connected. The idea of the “sandy beaches of time” came from the feeling of rolling around in the sand on the inclines. Imagine you’re floating in water and then you wash on shore. Then you’re on the sand. That’s a feeling of unexpected support. You’re lying passively and find yourself on solid ground somehow. That’s how I felt that I found myself (without trying or initiating a thought) supported unexpectedly in additional moments. This reminds me of the experience I had on a stronger dose in 2016 (same number of blotters but higher potency due to freshness) where I always felt “in the middle of my thought.” It’s like there’s a moment of height and openness at the peak of the thought where you expand open to figure out how you’re going to fit together the structural pieces of the highest level of organization of the thought. But I was continually in the middle of the thought and never finishing a thought, I felt. I tried a lot harder to have complete well formed thoughts back then too, so the experience would have been more notable. In general this time I was least excited or interested at all. Quite passive and peaceful, but not exploring with great energy or amusement. It was a lower dose. I thought it was going to be difficult and possibly be my first bad trip, but when I did them I saw as always that psychedelics are nice to me and weed is the only one who occasionally gets medieval. When I figure out my van and living situation I will definitely seek out more hoffmans and things like it, because they have a certain potential to make my mind work better and they don’t seem to make me insane at all. On weed I can picture some bad day it getting me into a fetal position, but on psychedelics I have a relaxed “power pose.”

I also slightly expanded my sense of unifying with the perceptual (and otherwise conceived/imagined) environment. I’m putting on equal footing (there’s that equal footing theme again… In an article (link) the author used the phrase on “equal footing” once.  I had an idea to explain the equal footing phenomenon but I forget what it was). I feel like my implicit understanding of “merge your awareness with the world around you” increased and so I didn’t have to try so hard to figure it out. At this point I started to reflect on the kind of spiritual poverty of the spiritual ideas and theories I had and would often think about. The ideas I have often come from a dim dull state of mind. Anyway the merging came at the same time as understanding objects on their own terms. So rather than forcing a single texture onto two objects to see them both, I would see both objects with their own unique shapes and the only thing bridging them together was my awareness. That felt like the cubism people talk about in psychedelics (by the way Brahms is notoriously full of time distortions and musical cubism and disintegrations. The very long lines and irregular rhythms (implying a much lengthier process to “resolve,” i.e., achieve a full round of symmetry) are like the decreased decay of stuff in the mindstream. You can use sentences, words, sounds, symbols in a way that sustain moments of that openness, the middle-of-the-thought, and use sleight of hand to keep it from compensating or closing back down.). So I’d put on equal footing perceptions and all the notions I had which would be replaced by syntheses. Like I’d see a plane out the window and have a notion of the distance I was from it and then the notion of the angle of the distance line on my body and the plane, maybe picturing the underside of the plane and then the point of view from the plane looking back down, and I thought these images were all valid, and with the cubism going on it seemed to put the plane and the skyspace relationship to me on equal footing as myself, so I would see and not identify with my physical body and it’s vantage point and I would begin to get a sense of omniscience. Normally I’d reject this and say, “Well, look, we can take the pieces of the collage and infer that there’s only one body with eyes who can see and a brain that can think… it’s not like the plane actually sees or thinks” and yet I was going beyond that somehow. The panpsychism I’ve long subscribed to is like particulate panpsychism. It’s just like molecules and atoms have basic building blocks of complicated mechanical chemical processes, likewise simple consciousness properties of the oxygen atom and the carbon atom are modified by complex activities. However, the way I always thought of it wasn’t very smart. It wasn’t distributed consciousness at all. Nor did the consciousnesses of particles grow or interact or form “consciousness molecules” out of consciousness atoms. It was only the ability of surrounding forces to dance upon a carbon atom’s surface that I could imagine some experience arising. As for the human state—there are billions of consciousnesses and you just happen to be the one seeing this or hearing that or having the feeling of talking. In fact, all these examples of phenomenal experience would be vastly too complicated. But it’s no problem when you don’t believe in binding to suppose that I’m not a single person who talks and hears single sounds, but I’m an army of tiny mind particles that contribute their own tiny dust threads to experience… an experience that remains unbound and separate from all the other threads. So something like mind dust.

The cubism, by the way, was like dissociation, except that, like with the sandy beaches of time rushing in to provide an unexpected moment of support, there was always some unexpected maximally abstract unity support rushing in to bridge the disperate cubist pieces. That bridge was found in ongoing openness to find out. It was like an exercise in faith, and, in turn trust and compassion.

Anyway, that’s one kind of panpsychism. Another kind is nihilistic. Something about my coefficients was altered. Something normally was disproportional in my approach to panpsychism. Something similarly was out of place in the approach to open individualism. Well, the hoffman seemed to tune me a bit and adjust the amount of belief and nihilism and so on I was going into it with to give me a fuller experience. It turns out that what I see as “taking at face value” is actually an important state of openness. One doesn’t truly take it at face value because one isn’t ever pretending to have complete knowledge, but one does take something without devoting so much resource to reconceiving it in order to conform to one’s beliefs. The hoffman experience was generally very in favor of bottom up mindfulness. Let go of socially motivated reasoning and imaginary conversations trying to prove yourself to ignorant people with no imaginations who want to ruin everything good… just put your energy into understanding something with openness and then you’ll see it. I got higher understandings or understandings I realized I otherwise wouldn’t get.

The experience really gave me a strong sense of the doom of my life while at the same time making me light hearted about it and trying to show me around. Normally I’m scared that a psychedelic is going to be like weed and be scary, but it never is. In fact the hoffman took me around my room to see that in some areas where there was some mess or something that I projected an ugly identity onto (like I see my shoes and the first thing I think is, “That’s asperger’s shoes. Those are the shoes someone with asperger’s wears.” So I have my social “identity disturbance” imbued into virtually all the objects around me. Any object that signifies someone else in my life is imbued with boogeymen and gremlins of the relationship I have with that person). I’m oppressed by my room and the needless flavoring of everything with stigma and shame… it’s so comprehensive that I’ve lost the sensitivity to it. It’s like a fish in water, I’m drowning in stigma to the point that I take it for granted and no longer realize there’s any other way of being. So the hoffman tried to show me around my room and show me there aren’t any boogey man and reconnect me to the personality I do have which isn’t aspergery and is fine and contradicts the stigmas. Every time I look in the mirror I see someone more attractive than I expected to see. I think this started in middle school. I always always always underestimate my appearance by quite a bit. And I load my self image with all those bad stigmas. Going to the mirror is like a reality check, but it’s worn out because I’m largely desensitized to it. But the hoffman helped me see that being aspergery or any other stigma was an unnecessary self-fulfilling trap I didn’t have to go down because I did have… I was in good standing and nothing meant I had to be aspergers. My posture my voice my skin etc.., all was fine.

But the hoffman did go over my life. I expected it would attack me about my relationship with my family (which I stigmatize myself for… “I must be some kind of deranged monster” is a load I begin every thought on the matter with) and turn me vegan, but it’s never what you expect. It wasn’t a fear based assault but it was really sane and reasonable. It gave me a sense of the trap I’m in. I ordinarily only feel one part of the trap at once, like I’m in a maze going from one dead end to another. But the hoffman gave me a sense of all the traps of my life I’m in at once. Yet I was lighthearted and amused and smiling about it. I was ego dead but I didn’t even know it. It’s like my ego left without making a sound. Another thing is that it isn’t necessarily key to have no ego, but it is key to be in the moment which is often conflated with having no ego. Like if you’re alone walking and having an inner monologue conversation, that’s probably being lost in thought having some imaginary future conversation and that exemplifies the problems and life-of-it’s-own of the ego. But it actually could be that one is checking into the present moment continuously and one is having that conversation for the nobody, for the consciousness. After all, the consciousness divided and packaged into different points of view and bodies in an audience is the same as the consciousness you have, so why not have the conversation before it? I used to regiment being in the moment, a certain grid of checkpoints of checking in. But that top-down systematic way of being mindful doesn’t work because I find shortcuts and seem to be beyond the age where I can keep going back to the beginner’s mind in a subject and question everything I know to the point where I am not allowed those shortcuts. Further those shortcuts are easy to take without knowing it. They masquerade as true mindfulness. So an informal bottom up spontaneous not regimented continuous mindfulness is important. I like the short ego stories mentioned… (to be continued… must use bathroom now)

I like the idea of short duration egos/stories Mike Johnson mentioned in his recent meditation article. I used to have long systematic stories with regimented moderately high frequency check ins with the present moment proportional to what I used to call “salience essentialism” (a silly name, but the idea of making some element of information that’s only found in a state of lots of reflection and skepticism and metacognitions essential). But, as I said, I can’t do that regimentation anymore, so I’m going with Mike Johnson’s idea of short egos linked together. To have short ego stories that remain close to the present it’s key not only to bring a story to a natural end soon but also to not linger on that ending. If you linger on that ending rather than immediately continuing the moment, keep it rolling in a new moment, then you end up just getting lost in a nothingness epilogue to the story. Useless. You can’t end and then stop with nothing to continue with. So key to keeping short ego stories is also continually making them. Always be shedding light on the situation (keep no secrets. The ego performer has no secrets to keep as the actor. Continually to unravel it in any situation it finds itself. Don’t worry about nullifying a previous performance…because the previous performance was never meant to fool you as complete reality. Hold onto no pretense, but continue to act while shedding light always. A dance without deceit.)

Rather than being mindful to grasp the moment, to pas a yes/no test, I be mindful anew each time. Every time I be mindful is a new way of being mindful, and it’s about quickly jumping to the moment. When you’re really mindful like this listening to Beethoven’s cello sonata, you can’t tell if it’s you that’s singing or the cello. It feels like your own mind almost. I used to be a yes/no tester. I would have a preconceived idea of reality I strove for. But now I’m not doing that. I’m letting go of all my notions and quickly coming to the moment with openness.

One more word on the cubism thing. It’s related very much, I think, to the feeling of open individualism as well as the sandy beaches of time thing because each item has with it it’s own competing structure. Normally we resolve things into one system, but this cubism takes different elements on-their-own-terms, which means there are terms and structures and systems and orientations attached to them. In these systems are simulated the ego and its orientation to things. It’s like when you have some words and are deciding what sentence to make of them you ordinarily subordinate certain words to other words (the main verb being at the highest level of organization), but instead this cubism would have competing sentences for different words. It wouldn’t force the collapse of one structure or system for the other. Likewise the feeling of always being in the middle of one’s thought (or the sandy beaches of time) is like the noncollapse of the thought structure. There are many overlapping thoughts, all of them in the middle, rather than one thought with a start and a finish spanning several moments. You see? I think a similar thing can explain the proliferation of selfhood in objects in one’s perceptual/imagined environment. You go beyond your ordinary selfhood sense structure and see no problem attaching it to multiple things, like anthropomorphizing things with your sense of orientation and first person perspective. This gives rise to a sense of perspective that is beyond seeing and hearing and all the ordinary things. Yet what is it? Alas, perspective as a concept is only as advanced as the abstraction of perceptions and imaginations and so on, so we don’t actually have a more advanced concept of perception/perspective-having. What we have is the abstraction that’s forced upon us by the cubism and multiplication of competing perspective-having structures attached to different objects. All we know is that whatever it is must go beyond any individual object and is seen only when you’re continually opening up to the idea by watching the cubism unfold. So it’s easy to understand how this is all just a conceptual trick of the mind, but it has a very good way of taking everything you know and all your beliefs and spinning those into the picture to convince you of something beyond all that still. And I really do like to believe the idea of a perspective that transcends my human situated perspective of sense organs and a center of imaginations. I’d like the floating above everything and seeing the symphony. I see how MC Escher pictures are very evocative here, because you have competing “structures” or competing whatevers…  competing resolutions. MC Escher is a form of cubism in this way.

Another thing I notice is a decrease in bad compulsions. Generally psychedelics relieve anxiety and obsessions and stuff like that. I have this nasty habit of looking at attractive people and getting a pang of pain and loneliness and stuff. My work involves me being on social media all day long, so I often see a lot of attractive people and it’s just a pang of badness. But fighting with the compulsion is no good either. Flee it. I’ve got to stop correcting past mistakes. Short ego story. Don’t go down one road and then smack your forehead and then reverse and go back down another road. Nobody wants to see you back up. It’s not valuable. You’re not submitting or apologizing to anyone. Once you go down one road simply poof out of existence and then poof back into existence on the right road. No ego story of grinding corrections and punishments and obstacles. Just skip ahead to the right spot the moment you notice a better spot. Ordinarily seeing or hearing attractive people makes me tense up and go ouch and feel a dose of desperation and so on. This time I’m not doing that. I find that I’m lucky that I haven’t had that and a state of not clinging and so on is naturally here (I’m not anxiously monitoring my clinging level). I think it’s good to just zip to the right moment, the right thought and not spend time wrestling with the thing trying to undo it explicitly. Learn the habit of bypassing it, not reversing it. Don’t even expedite reversal. There should be no struggle to correct anything. Rather just jump freely to a better state of mind. But that’s easier said than done. I think it’s very hard to see the possibility of freedom in the present when faced with very strong recurrent thoughts or states of mind that one doesn’t want. It feels like the only hope of getting out of there is by contending with it, reversing it. But I’m suggesting that actually one can unlearn ever going down the wrong path in the first place (as opposed to learning to make the mistake and then the correction) and that is found in the present, the elusive present we overlook (or underlook). In fact, the present moment isn’t known to you yet while you’re still trying to struggle to escape the undesirable thought pattern. Trust that it will show you the way and open up to you as you open up to it. It will progressively open up, and you’ll say, “Oh, I see now.” 

So short stories are good, being in the moment is good. The intentional object is particularly tyrannical (ref) when it lives in a long story. Short stories can still have intentional objects. Things can have purposes, there can be a point, but the point should be found in the present (or the very very near future). When you find yourself having imaginary conversations for the future, then quickly start speaking that to the present. Whom are you talking to? Nobody. The nobody of the now (or yourself, or the non-people of the now) is a perfectly interesting audience.  You have within your consciousness basically what any audience can actually supply anyway. Consciousness differentiated through filters of points of view and personality and so on is only just the same as what you have in your “solitary” conversation.

Well anyway, I found myself having a bit of a love for the present. I like knowing that fulfillment is found in the present. It is beautiful and wholesome. I like not being chained to anxieties and compulsions. I like the spontaneousness of the higher rate of mindfulness. I don’t normally have so much mindfulness and trying with much effort to be mindful backfires. As explained above about reversing mistakes, today I was quickly and without making a fuss finding myself snapping back into the present. Rather than trying to make an ordeal of an error report trying to diagnose the lapse in mindfulness and see to it that it doesn’t happen again, I let go of that controlling and just join the present moment “ready to rock” as [person] from [previous job] would put it.

Here’s part of the trip report. I wrote the other half of it in a paper notebook:

5:10PM I recorded everything earlier in a notebook.

Wow so much easier to type fast. Anyway I see how the ego and the self, I created a dark scary world of doubt and fear and shame for this Bill character. It’s just a character. Bring as many emotional resolutions as possible to make the story have as happy an ending as can be, but ultimately just don’t forget it’s all fiction.

And I guess that’s key. The fears of the hellishness of being a “bad human” and so on…all fictions of the Bill story in the world, in consensus reality. Make the story look nice, but see through it. It’s just a story for some TV viewer. I’m so predictable, what I’m paranoid about, what my hang ups are, etc… How the grass is greener on the other side of being social.

But this trip, rather than dipping me in guilt and attacking me with my own problems is actually more like a refresher on how these places aren’t full of boogeymen like I think they are, and if I just realized this I’d have a better day. But ultimately the desperateness and the loneliness and so on…gosh what a drag. On and on and on being upset about my life. I cultivate a sense of loss before fulfilling it. I should instead not have any needs and just pursue excitement… It’s interesting to think about whether you can get anywhere in life or have a very interesting time without those needs and voids held open by fear.

5:19PM I think I watch Minecraft playthroughs as a surrogate for socializing. Now without getting emotional or caught up in the Bill story, let’s just assess whether this is necessary.

5:25PM I’m listening to music. I’m admiring the majesty of some things in it. CPE bach. Just like Huxley said about my nonself being the non self of that chair leg, I identify as a non self with the non self of the grand music at points. Anyway, I notice how a lot of my enjoyment of music is really grinding and unpleasant. Forceful and full of pain like fighting through wounds, forcing your way through barbed wire. It’s senseless, isn’t it? If I can control it and enjoy music without this forceful stuff, this suffering forcefulness and longing and neediness and narrowness.

5:30PM Those headphones cause such misery. I get lost in those things. I’m getting a bit morbid, aren’t I? I’m not coming down but I’m tired and maybe my blood sugar is lower or something.

9:51PM Watched the Terence McKenna in Prague with Ram Das and Shulgin and others (link 1, link 2). Fascinating. Then I listened to this I noticed how this time I did acid my mind didn’t expand very much at all. I feel old and like my brain is stuck in certain ways of seeing things. I do have a gentle calling to feel myself situated in terms of nature and evolution and the mystery of the universe…I just want to see the open night sky like our ancestors did, but not clouded by all these paved roads and jobs and clocks and so on. Missing the moment for some future goal, measured by time and streets and so on. I liked what Watts said about playing a musical instrument for the enjoyment of music and not to do secondary things like make money or impress an audience. Now one could say that their goal is to impress audiences and so one isn’t “playing music” but one is “impressing audiences” and happening to play music. But I like the idea of only playing music in an innocent way because of the pleasure the noise gives. Unlocking the song by learning the music is rewarded by the music as it comes along. Not the prospect of performing or this becoming a dance of your ego or something. That’s kind of the problem. At least not living acts for the present well enough. That’s what I meant a couple weeks ago about having present moment self goals. Have goals for the moment. Don’t do stuff for later. The goal shouldn’t be set on some fulfillment of something later on. Why? Because people who say things like that have broken heads and my head is broken so I say stuff like that. Anyway, when I play music it should be to produce sound. When I try to get a self image, a social ego, a sense of my social personality, it shouldn’t be aimed at a future date. I should be genuine where I am, even if I’m alone. That is the moment. When it happens, it isn’t practice for some future performance. I’m not scripting. Rather, that is it. That was the moment to make the joke or be clever or do something. If I’m alone, that’s who I do it for. I do it for myself and nobody. I don’t do it for anybody, at least nobody to be abstracted and conceived in a later date. What happens happens then…what happens in the moment stays in the moment. Right now, who am I journaling with? Whom am I talking to? Wow, I can’t even believe I’ve got the depth to question that. Above I mentioned how not expanded my mind felt. Well I’m not very reflective, and the fact I just brought up the question who I am journaling for shows that thing. A lot of life has been lived in these journals. Some good, a lot bad. I can imagine myself throwing my journals away. I can imagine my laptop getting stolen or destroyed or lost. I no longer am hoarding up notes on philosophy projects. So what is this all for? Well, it’s all for itself. And right now it feels better. This feels like a good use of my time and a legitimate experience of living. Nothing lacks. I don’t need to add on some need to escape here and strive for a better place. Apples and oranges. This is adequate in itself. What I do, I must enjoy doing for the sake of itself. I don’t read books to build a vocabulary and a wit so I can talk to people. I have to enjoy reading the books and having that vocabulary and wit as the reader. Not for some future moment. The journey of a book isn’t an overture to something else. It is the journey. I need really to start becoming intrinsically motivated by everything I do, see things as ends in themselves. Really end. Not mindfulness to some other place. I make this mistake all the time. I think of the future now, of the future present moment mindfulness state. I’ve got to enjoy the mindfulness I already have before I can progress further…or rather before it can progress to unfold and intensify. I have to appreciate the experience of education I’m getting by reading a book, raw education however unglamorous and rudimentary, before my education can grow and intensify.

Sunk cost is big when trying to improve yourself (referring back to Alan Watts talk there). If I haven’t already implemented these notes about living in the present moment, then why do I think I can? Seems like the game has run stale. I’ve been narrowly focused and in sunk cost and escapism and I need to just let go of the outcome and step back and observe. Just like what I said about the stand-up comedian’s ego filtering out the amount of feedback based on how massively they’d have to renovate their act—they’re unwilling to open themselves up to just assess what’s wrong and fix it because they’re trying to open up to a small amount, one repair guy and see what he says and see if he recommends a follow up repair guy when he can’t figure it out, and then two slightly more in-depth expert repair guys come by and so on….why is this progression of repairmen economical? It is if you have no idea what’s wrong with your electricity in your house, but if you are a standup comedian and your ability to correct your act depends on your ability to recognize what’s wrong with it and you have access to that consultation, why limit yourself by peeking through a half closed eye? Why not just open up and see the whole situation? You won’t waste time…oh so much time you’ll spend fighting your way back up from the later stage repair men to earlier repair men…correcting later stage specific advanced diagnoses but still something’s wrong but it’s simpler than before. Just always wrestling with the errors in your performance trying to keep them in the simple no biggie zone rather than in the serious fail zone. But if only you were willing to open your eyes fully to see the true extent of the problems, then you could fix them all.

10:30PM Down with an edible. Wow, surprised how powerful the acid still is. Let’s see I took one at 12:33PM and the other at 1:49PM. Well, and I just took an edible. A tinge of regret because it’ll dull and otherwise contaminate the acid, but I’m getting tired so it wasn’t like I was going to get much out of it anyway. Alas, I’m still looking for gold to fill my notebooks for for later reading. I still take notes for the future. I should see notes as what they really are, which is just prosthetics for the experience of narratives in the present moment. Nothing more. (And I’m often blind to that possibility! I’m blind to the potential of the present! I only think in terms of future stuff. I just overlook the present.)

10:36 Wow that Alan Watts talk though. I know I always can’t help but put in my disclaimers. I don’t even feel like going through the various examples of why I have critical reasoning bla bla bla (don’t think of me as a stupid sheep). Just how helpless I seem to be in my current mode of doing things to get myself to live in the present and for the present. I don’t make decisions. I don’t decide what meanings my words have. I rather sit there passively waiting for the right words to come and fill in. I could do with some asserting myself more. But when the moment is right, when it gives energy rather than drains.

And rather than striving for an answer for a theory about consciousness or something or reality or whatever crazy… that is so rewarding that it can be done for itself in the moment. Think about consciousness. The mystery of the ever elusive background. The unknown is stimulating. It is exciting. Seeing the implications of the unknown and questioning old frameworks is enjoyable. It just is. 🙂

11:30PM Just took my second edible. (Saw: Alan Watts – Nature of God)

12:31AM Only do things for the now. Don’t solve problems for the future. Propose solutions for the future in the now. It’s a present act. You’re just exercising talking and proposing and speculating recreationally for the present. You ‘re not putting your will into the future. And the idea I have is that the bleakness of my life is in my head. Living in a van can be positive. I can have a happier social life. But doubts just feed. They’re demonic. They love sadness like heroin. They love to feed on the anxieties about not being able to make friends, of how poor my track record has been, how my life used to be in my control and going in a direction has now fallen so dramatically in a different way….The doubt tempts you. The decisions stop being made in the present moment. IT says “Hold on now. Think about this…” as it proceeds, foot in the door, to tempt you to sadness and doubt, as if there’s some social reward for having a sufficiently pessimistic view.

Anti-Tolerance Drugs

It would indeed be extraordinary if – alone among the neurotransmitter systems of the brain – the endogenous opioid families were immune from dysfunction. Enkephalins are critical to “basal hedonic tone” i.e. whether we naturally feel happy or sad. Yet the therapeutic implications of a recognition that dysfunctional endogenous opioid systems underlie a spectrum of anxiety-disorders and depression are too radical – at present – for the medical establishment to contemplate. In consequence, the use of opioid-based pharmacotherapies for “psychological” pain is officially taboo. The unique efficacy of opioids in banishing mental distress is neglected. Their unrivalled efficacy in treating “physical” nociceptive pain is grudgingly accepted.

 

Future Opioids, by David Pearce

Albert Camus wrote that the only serious question is whether to kill yourself or not. Tom Robbins wrote that the only serious question is whether time has a beginning and an end. Camus clearly got up on the wrong side of bed, and Robbins must have forgotten to set the alarm. There is only one serious question. And that is: Who knows how to make love stay? [emphasis mine] Answer me that and I will tell you whether or not to kill yourself.

 

– Still Life with Woodpecker by Tom Robbins

As eloquently argued by David Pearce in Future Opioids, the problem with opioids and other euphoriant drugs is not that they make you feel good, but that the positive feelings are short lived. In their stead, tolerance, withdrawal, and dependence ultimately set in after repeated use. We take the position that these negatives are not a necessary outcome of feeling free from physical or psychological malaise, for the brain has clever negative feedback mechanisms that prevent us from wireheading chemically. Rather, we believe that tackling these negative feedback mechanisms directly might be they key that unlocks never-ending bliss. Note that even if excellent anti-tolerance drugs were to be developed and commercialized for therapeutic use, we would still need to find solutions to the problems posed by wireheading. Specifically, disabling the negative feedback mechanisms in place that prevent us from feeling well all the time still leaves unsolved the problem of avoiding getting stuck in counterproductive patterns of behavior and becoming at risk of turning into a pure replicator (for proposed solutions to these problems see: Wireheading Done Right). Still, we strongly believe that finding safe and effective anti-tolerance drugs is a step in the right direction in the battle against suffering throughout the living world.

We thus provide the following list of promising anti-tolerance drugs in the hopes of: (1) piquing the interest of budding psychopharmacologists who may be weighting-in on promising research leads, (2) show a proof of concept against the fake and fatalistic truism that “what goes up has to go down” (cf. The Hedonistic Imperative), and last but not least, (3) provide hope to people suffering from physical or psychological distress who would benefit from anti-tolerance drugs, such as those who experience treatment-resistant anxiety, depression, chronic pain, or chemical dependence.

It is worth noting that this list is just a draft, and we will continue to revise it as the science progresses. Please let us know in the comment section if you are aware of compounds not included in this list (of special interest are tier 1 and tier 2 compounds).

Tier System

The list is organized by tiers. Tier 1 includes compounds for which there is evidence that they can reverse tolerance. Tier 2 deals with compounds that seem to either block or attenuate the development of tolerance, meaning that co-administering them with a euphoric agonist reduces the speed at which this euphoriant creates tolerance. Tier 3 includes potentiators. That is, compounds that enhance the effects of other substances without at the same time increasing tolerance to the extent that would be expected given the intensity of the subjective effects. Tier 4 lists compounds that, while not exactly tolerance-related, are still worth mentioning by virtue of reducing the intensity of drug withdrawals. And finally, Tier 5 includes euphoriants that have a favorable pharmacological profile relative to their alternatives, although will still produce tolerance long-term. Typically, a substance belonging to Tier X will also belong to Tier X + 1 and above (except for Tier 5) but we omit repetitions to avoid redundancy (e.g. proglumide not only reverses tolerance, but prevents tolerance, is a potentiatior, and reduces withdrawals).

Opioid System

Tier 1

  1. Ibogaine (see: Low dose treatment)
  2. Proglumide
  3. Naltrexone (specifically in Ultra Low Doses)
  4. Ibudilast (AV-411)

Tier 2

  1. Agmatine (may also help with chronic pain on its own)
  2. Curcumin (found in Turmeric; only works in high-availability forms)
  3. Thymoquinone (found in Nigella Sativa/black seed oil)

Tier 3

  1. DXM (specially potentiates the analgesia, which may be of use for chronic pain sufferers)
  2. Hydroxyzine (beware of its effects on sufferers of Akathisia/Restless Legs Syndrome; also bad in the long term for one’s cognitive capacity)
  3. L-Tyrosine
  4. Magnesium (possibly tier 2 but only weakly so)

Tier 4

  1. L-Aspartic Acid
  2. Ashwagandha
  3. JDTic
  4. Gabapentin
  5. Clonidine

Tier 5

  1. Tianeptine (its effects on the delta opioid receptor attenuates its tolerance when used in therapeutic doses)
  2. Mitragynine (thanks to its partial agonism rather than full agonism it is less dangerous in high doses relative to alternatives; specifically, mitragyne does not have dangerous respiratory depression properties on its own, so switching heroin addicts to it would arguably save countless lives)

 

GABA System

Tier 1

  1. Flumazenil (note: very dose-dependent)

Tier 2

  1. Tranylcypromine
  2. Ginsenosides
  3. Homotaurine
  4. Fasoracetam

Tier 3

  1. Dihydromyricetin

See also.

Dopamine System

Insufficient datapoints for a tier system. Here are the few promising leads:

  1. D-serin
  2. D-cycloserine
  3. Sulbutamine
  4. Bromantane
  5. Memantine

See also.


Tanks to Adam Karlovsky for help compiling these lists.