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.


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.


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!


Making Amazing Recreational Drug Cocktails


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.



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 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.


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.


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?


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).


A Big State-Space of Consciousness

Kenneth Shinozuka of Blank Horizons asks: Andrés, how long do you think it’ll take to fully map out the state space of consciousness? A thousand or a million years?

The state-space of consciousness is unimaginably large (and yet finite)

I think we will discover the core principles of a foundational theory of consciousness within a century or so. That is, we might find plausible solutions to Mike Johnsons’ 8 subproblems of consciousness and experimentally verify a specific formal theory of consciousness before 2100. That said, there is a very large distance between proving a certain formal theory of consciousness and having a good grasp of the state-space of consciousness.

Knowing Maxwell’s equations gives you a formal theory of electromagnetism. But even then, photons are hidden as an implication of the formalism; you need to do some work to find them in it. And that’s the tip of the iceberg; you would also find hidden in the formalism an array of exotic electromagnetic behavior that arise in unusual physical conditions such as those produced by metamaterials. The formalism is a first step to establish the fundamental constraints for what’s possible. What follows is filling in the gaps between the limits of physical possibility, which is a truly fantastical enterprise considering the range of possible permutations.Island_of_Stability_derived_from_Zagrebaev

A useful analogy here might be: even though we know all of the basic stable elements and many of their properties, we have only started mapping out the space of possible small molecules (e.g. there are ~10^60 bioactive drugs that have never been tested), and have yet to even begin the project in earnest of understanding what proteins can do. Or consider the number of options there are to make high-entropy alloys (alloys made with five or more metals). Or all the ways in which snowflakes of various materials can form, meaning that even when you are studying a single material it can form crystal structures of an incredibly varied nature. And then take into account the emergence of additional collective properties: physical systems can display a dazzling array of emergent exotic effects, from superconductivity and superradiance to Bose-Einstein condensates and fusion chain reactions. Exploring the state-space of material configurations and their emergent properties entails facing a combinatorial explosion of unexpected phenomena.

And this is the case in physics even though we know for a fact that there are only a bit over a hundred possible building blocks (i.e. the elements).

In the province of the mind, we do not yet have even that level of understanding. When it comes to the state-space of consciousness we do not have a corresponding credible “periodic table of qualia”. The range of possible experiences in normal everyday life is astronomical. Even so, the set of possible human sober experiences is a vanishing fraction of the set of possible DMT trips, which is itself a vanishing fraction of the set of possible DMT + LSD + ketamine + TMS + optogenetics + Generalized Wada Test + brain surgery experiences. Brace yourself for a state-space that grows supergeometrically with each variable you introduce.

If we are to truly grasp the state-space of consciousness, we should also take into account non-human animal qualia. And then further still, due to dual-aspect monism, we will need to go into things like understanding that high-entropy alloys themselves have qualia, and then Jupiter Brains, and Mike’s Fraggers, and Black Holes, and quantum fields in the inflation period, and so on. This entails a combinatorial explosion of the likes I don’t believe anyone is really grasping at the moment. We are talking about a monumental “monster” state-space far beyond the size of even the wildest dreams of full-time dreamers. So, I’d say -honestly- I think that mapping out the state-space of consciousness is going to take millions of years.

But isn’t the state-space of consciousness infinite, you ask?

Alas, no. There are two core limiting factors here – one is the speed of light (which entails the existence of gravitational collapse and hence limits to how much matter you can arrange in complex ways before a black hole arises) and the second one is quantum (de)coherence. If phenomenal binding requires fundamental physical properties such as quantum coherence, there will be a maximum limit to how much matter you can bind into a unitary “moment of experience“. Who knows what the limit is! But I doubt it’s the size of a galaxy – perhaps it is more like a Jupiter Brain, or maybe just the size of a large building. This greatly reduces the state-space of consciousness; after all, something finite, no matter how large, is infinitely smaller than something infinite!

But what if reality is continuous? Doesn’t that entail an infinite state-space?

I do not think that the discrete/continuous distinction meaningfully impacts the size of the state-space of consciousness. The reason is that at some point of degree of similarity between experiences you get “just noticeable differences” (JNDs). Even with the tiniest hint of true continuity in consciousness, the state-space would be infinite as a result. But the vast majority of those differences won’t matter: they can be swept under the rug to an extent because they can’t actually be “distinguished from the inside”. To make a good discrete approximation of the state-space, we would just need to divide the state-space into regions of equal area such that their diameter is a JND.15965332_1246551232103698_2088025318638395407_n


In summary, the state-space of consciousness is insanely large but not infinite. While I do think it is possible that the core underlying principles of consciousness (i.e. an empirically-adequate formalism) will be discovered this century or the next, I do not anticipate a substantive map of the state-space of consciousness to be available anytime soon. A truly comprehensive map would, I suspect, be only possible after millions of years of civilizational investment on the task.

Three Interesting Math Problems to Work on While on LSD

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

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

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