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, 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Cuscohydrine, Hygrine, 4-NEMD, Aceburic Acid, Amfecloral, Aprobarbital, Arfendazam, Benzobarbital, Benzylbutylbarbituate, Brallobarbital, Brophebarbital, Buthalitol, Carbubarb, Climazolam, Cyclobarbital, Cyclopentobarbital, and Acid (i.e. regular LSD).


Why I think the Foundational Research Institute should rethink its approach

by Mike Johnson

The following is my considered evaluation of the Foundational Research Institute, circa July 2017. I discuss its goal, where I foresee things going wrong with how it defines suffering, and what it could do to avoid these problems.

TL;DR version: functionalism (“consciousness is the sum-total of the functional properties of our brains”) sounds a lot better than it actually turns out to be in practice. In particular, functionalism makes it impossible to define ethics & suffering in a way that can mediate disagreements.

I. What is the Foundational Research Institute?

The Foundational Research Institute (FRI) is a Berlin-based group that “conducts research on how to best reduce the suffering of sentient beings in the near and far future.” Executive Director Max Daniel introduced them at EA Global Boston as “the only EA organization which at an organizational level has the mission of focusing on reducing s-risk.” S-risks are, according to Daniel, “risks where an adverse outcome would bring about suffering on an astronomical scale, vastly exceeding all suffering that has existed on Earth so far.”

Essentially, FRI wants to become the research arm of suffering-focused ethics, and help prevent artificial general intelligence (AGI) failure-modes which might produce suffering on a cosmic scale.

What I like about FRI:

While I have serious qualms about FRI’s research framework, I think the people behind FRI deserve a lot of credit- they seem to be serious people, working hard to build something good. In particular, I want to give them a shoutout for three things:

  • First, FRI takes suffering seriously, and I think that’s important. When times are good, we tend to forget how tongue-chewingly horrific suffering can be. S-risks seem particularly horrifying.
  • Second, FRI isn’t afraid of being weird. FRI has been working on s-risk research for a few years now, and if people are starting to come around to the idea that s-risks are worth thinking about, much of the credit goes to FRI.
  • Third, I have great personal respect for Brian Tomasik, one of FRI’s co-founders. I’ve found him highly thoughtful, generous in debates, and unfailingly principled. In particular, he’s always willing to bite the bullet and work ideas out to their logical end, even if it involves repugnant conclusions.

What is FRI’s research framework?

FRI believes in analytic functionalism, or what David Chalmers calls “Type-A materialism”. Essentially, what this means is there’s no ’theoretical essence’ to consciousness; rather, consciousness is the sum-total of the functional properties of our brains. Since ‘functional properties’ are rather vague, this means consciousness itself is rather vague, in the same way words like “life,” “justice,” and “virtue” are messy and vague.

Brian suggests that this vagueness means there’s an inherently subjective, perhaps arbitrary element to how we define consciousness:

Analytic functionalism looks for functional processes in the brain that roughly capture what we mean by words like “awareness”, “happy”, etc., in a similar way as a biologist may look for precise properties of replicators that roughly capture what we mean by “life”. Just as there can be room for fuzziness about where exactly to draw the boundaries around “life”, different analytic functionalists may have different opinions about where to define the boundaries of “consciousness” and other mental states. This is why consciousness is “up to us to define”. There’s no hard problem of consciousness for the same reason there’s no hard problem of life: consciousness is just a high-level word that we use to refer to lots of detailed processes, and it doesn’t mean anything in addition to those processes.

Finally, Brian argues that the phenomenology of consciousness is identical with the phenomenology of computation:

I know that I’m conscious. I also know, from neuroscience combined with Occam’s razor, that my consciousness consists only of material operations in my brain — probably mostly patterns of neuronal firing that help process inputs, compute intermediate ideas, and produce behavioral outputs. Thus, I can see that consciousness is just the first-person view of certain kinds of computations — as Eliezer Yudkowsky puts it, “How An Algorithm Feels From Inside“. Consciousness is not something separate from or epiphenomenal to these computations. It is these computations, just from their own perspective of trying to think about themselves.


In other words, consciousness is what minds compute. Consciousness is the collection of input operations, intermediate processing, and output behaviors that an entity performs.

And if consciousness is all these things, so too is suffering. Which means suffering is computational, yet also inherently fuzzy, and at least a bit arbitrary; a leaky high-level reification impossible to speak about accurately, since there’s no formal, objective “ground truth”.

II. Why do I worry about FRI’s research framework?

In short, I think FRI has a worthy goal and good people, but its metaphysics actively prevent making progress toward that goal. The following describes why I think that, drawing heavily on Brian’s writings (of FRI’s researchers, Brian seems the most focused on metaphysics):

Note: FRI is not the only EA organization which holds functionalist views on consciousness; much of the following critique would also apply to e.g. MIRI, FHI, and OpenPhil. I focus on FRI because (1) Brian’s writings on consciousness & functionalism have been hugely influential in the community, and are clear enough *to* criticize; (2) the fact that FRI is particularly clear about what it cares about- suffering- allows a particularly clear critique about what problems it will run into with functionalism; (3) I believe FRI is at the forefront of an important cause area which has not crystallized yet, and I think it’s critically important to get these objections bouncing around this subcommunity.

Objection 1: Motte-and-bailey

Brian: “Consciousness is not a thing which exists ‘out there’ or even a separate property of matter; it’s a definitional category into which we classify minds. ‘Is this digital mind really conscious?’ is analogous to ‘Is a rock that people use to eat on really a table?’ [However,] That consciousness is a cluster in thingspace rather than a concrete property of the world does not make reducing suffering less important.”

The FRI model seems to imply that suffering is ineffable enough such that we can’t have an objective definition, yet sufficiently effable that we can coherently talk and care about it. This attempt to have it both ways seems contradictory, or at least in deep tension.

Indeed, I’d argue that the degree to which you can care about something is proportional to the degree to which you can define it objectively. E.g., If I say that “gnireffus” is literally the most terrible thing in the cosmos, that we should spread gnireffus-focused ethics, and that minimizing g-risks (far-future scenarios which involve large amounts of gnireffus) is a moral imperative, but also that what is and what and isn’t gnireffus is rather subjective with no privileged definition, and it’s impossible to objectively tell if a physical system exhibits gnireffus, you might raise any number of objections. This is not an exact metaphor for FRI’s position, but I worry that FRI’s work leans on the intuition that suffering is real and we can speak coherently about it, to a degree greater than its metaphysics formally allow.

Max Daniel (personal communication) suggests that we’re comfortable with a degree of ineffability in other contexts; “Brian claims that the concept of suffering shares the allegedly problematic properties with the concept of a table. But it seems a stretch to say that the alleged tension is problematic when talking about tables. So why would it be problematic when talking about suffering?” However, if we take the anti-realist view that suffering is ‘merely’ a node in the network of language, we have to live with the consequences of this: that ‘suffering’ will lose meaning as we take it away from the network in which it’s embedded (Wittgenstein). But FRI wants to do exactly this, to speak about suffering in the context of AGIs, simulated brains, even video game characters.

We can be anti-realists about suffering (suffering-is-a-node-in-the-network-of-language), or we can argue that we can talk coherently about suffering in novel contexts (AGIs, mind crime, aliens, and so on), but it seems inherently troublesome to claim we can do both at the same time.

Objection 2: Intuition duels

Two people can agree on FRI’s position that there is no objective fact of the matter about what suffering is (no privileged definition), but this also means they have no way of coming to any consensus on the object-level question of whether something can suffer. This isn’t just an academic point: Brian has written extensively about how he believes non-human animals can and do suffer extensively, whereas Yudkowsky (who holds computationalist views, like Brian) has written about how he’s confident that animals are not conscious and cannot suffer, due to their lack of higher-order reasoning.

And if functionalism is having trouble adjudicating the easy cases of suffering–whether monkeys can suffer, or whether dogs can— it doesn’t have a sliver of a chance at dealing with the upcoming hard cases of suffering: whether a given AGI is suffering, or engaging in mind crime; whether a whole-brain emulation (WBE) or synthetic organism or emergent intelligence that doesn’t have the capacity to tell us how it feels (or that we don’t have the capacity to understand) is suffering; if any aliens that we meet in the future can suffer; whether changing the internal architecture of our qualia reports means we’re also changing our qualia; and so on.

In short, FRI’s theory of consciousness isn’t actually a theory of consciousness at all, since it doesn’t do the thing we need a theory of consciousness to do: adjudicate disagreements in a principled way. Instead, it gives up any claim on the sorts of objective facts which could in principle adjudicate disagreements.

This is a source of friction in EA today, but it’s mitigated by the sense that

(1) The EA pie is growing, so it’s better to ignore disagreements than pick fights;

(2) Disagreements over the definition of suffering don’t really matter yet, since we haven’t gotten into the business of making morally-relevant synthetic beings (that we know of) that might be unable to vocalize their suffering.

If the perception of one or both of these conditions change, the lack of some disagreement-adjudicating theory of suffering will matter quite a lot.

Objection 3: Convergence requires common truth

Mike: “[W]hat makes one definition of consciousness better than another? How should we evaluate them?”

Brian: “Consilience among our feelings of empathy, principles of non-discrimination, understandings of cognitive science, etc. It’s similar to the question of what makes one definition of justice or virtue better than another.”

Brian is hoping that affective neuroscience will slowly converge to accurate views on suffering as more and better data about sentience and pain accumulates. But convergence to truth implies something (objective) driving the convergence- in this way, Brian’s framework still seems to require an objective truth of the matter, even though he disclaims most of the benefits of assuming this.

Objection 4: Assuming that consciousness is a reification produces more confusion, not less

Brian: “Consciousness is not a reified thing; it’s not a physical property of the universe that just exists intrinsically. Rather, instances of consciousness are algorithms that are implemented in specific steps. … Consciousness involves specific things that brains do.”

Brian argues that we treat conscious/phenomenology as more ‘real’ than it is. Traditionally, whenever we’ve discovered something is a leaky reification and shouldn’t be treated as ‘too real’, we’ve been able to break it down into more coherent constituent pieces we can treat as real. Life, for instance, wasn’t due to élan vital but a bundle of self-organizing properties & dynamics which generally co-occur. But carrying out this “de-reification” process on consciousness– enumerating its coherent constituent pieces– has proven difficult, especially if we want to preserve some way to speak cogently about suffering.

Speaking for myself, the more I stared into the depths of functionalism, the less certain everything about moral value became– and arguably, I see the same trajectory in Brian’s work and Luke Muehlhauser’s report. Their model uncertainty has seemingly become larger as they’ve looked into techniques for how to “de-reify” consciousness while preserving some flavor of moral value, not smaller. Brian and Luke seem to interpret this as evidence that moral value is intractably complicated, but this is also consistent with consciousness not being a reification, and instead being a real thing. Trying to “de-reify” something that’s not a reification will produce deep confusion, just as surely trying to treat a reification as ‘more real’ than it actually is will.

Edsger W. Dijkstra famously noted that “The purpose of abstraction is not to be vague, but to create a new semantic level in which one can be absolutely precise.” And so if our ways of talking about moral value fail to ‘carve reality at the joints’- then by all means let’s build better ones, rather than giving up on precision.

Objection 5: The Hard Problem of Consciousness is a red herring

Brian spends a lot of time discussing Chalmers’ “Hard Problem of Consciousness”, i.e. the question of why we’re subjectively conscious, and seems to base at least part of his conclusion on not finding this question compelling— he suggests “There’s no hard problem of consciousness for the same reason there’s no hard problem of life: consciousness is just a high-level word that we use to refer to lots of detailed processes, and it doesn’t mean anything in addition to those processes.” I.e., no ‘why’ is necessary; when we take consciousness and subtract out the details of the brain, we’re left with an empty set.

But I think the “Hard Problem” isn’t helpful as a contrastive centerpiece, since it’s unclear what the problem is, and whether it’s analytic or empirical, a statement about cognition or about physics. At the Qualia Research Institute (QRI), we don’t talk much about the Hard Problem; instead, we talk about Qualia Formalism, or the idea that any phenomenological state can be crisply and precisely represented by some mathematical object. I suspect this would be a better foil for Brian’s work than the Hard Problem.

Objection 6: Mapping to reality

Brian argues that consciousness should be defined at the functional/computational level: given a Turing machine, or neural network, the right ‘code’ will produce consciousness. But the problem is that this doesn’t lead to a theory which can ‘compile’ to physics. Consider the following:

Imagine you have a bag of popcorn. Now shake it. There will exist a certain ad-hoc interpretation of bag-of-popcorn-as-computational-system where you just simulated someone getting tortured, and other interpretations that don’t imply that. Did you torture anyone? If you’re a computationalist, no clear answer exists- you both did, and did not, torture someone. This sounds like a ridiculous edge-case that would never come up in real life, but in reality it comes up all the time, since there is no principled way to *objectively derive* what computation(s) any physical system is performing.

I don’t think this is an outlandish view of functionalism; Brian suggests much the same in How to Interpret a Physical System as a Mind“Physicalist views that directly map from physics to moral value are relatively simple to understand. Functionalism is more complex, because it maps from physics to computations to moral value. Moreover, while physics is real and objective, computations are fictional and ‘observer-relative’ (to use John Searle’s terminology). There’s no objective meaning to ‘the computation that this physical system is implementing’ (unless you’re referring to the specific equations of physics that the system is playing out).”

Gordon McCabe (McCabe 2004) provides a more formal argument to this effect— that precisely mapping between physical processes and (Turing-level) computational processes is inherently impossible— in the context of simulations. First, McCabe notes that:

[T]here is a one-[to-]many correspondence between the logical states [of a computer] and the exact electronic states of computer memory. Although there are bijective mappings between numbers and the logical states of computer memory, there are no bijective mappings between numbers and the exact electronic states of memory.

This lack of an exact bijective mapping means that subjective interpretation necessarily creeps in, and so a computational simulation of a physical system can’t be ‘about’ that system in any rigorous way:

In a computer simulation, the values of the physical quantities possessed by the simulated system are represented by the combined states of multiple bits in computer memory. However, the combined states of multiple bits in computer memory only represent numbers because they are deemed to do so under a numeric interpretation. There are many different interpretations of the combined states of multiple bits in computer memory. If the numbers represented by a digital computer are interpretation-dependent, they cannot be objective physical properties. Hence, there can be no objective relationship between the changing pattern of multiple bit-states in computer memory, and the changing pattern of quantity-values of a simulated physical system.

McCabe concludes that, metaphysically speaking,

A digital computer simulation of a physical system cannot exist as, (does not possess the properties and relationships of), anything else other than a physical process occurring upon the components of a computer. In the contemporary case of an electronic digital computer, a simulation cannot exist as anything else other than an electronic physical process occurring upon the components and circuitry of a computer.

Where does this leave ethics? In Flavors of Computation Are Flavors of Consciousness, Brian notes that “In some sense all I’ve proposed here is to think of different flavors of computation as being various flavors of consciousness. But this still leaves the question: Which flavors of computation matter most? Clearly whatever computations happen when a person is in pain are vastly more important than what’s happening in a brain on a lazy afternoon. How can we capture that difference?”

But if Brian grants the former point- that “There’s no objective meaning to ‘the computation that this physical system is implementing’”– then this latter task of figuring out “which flavors of computation matter most” is provably impossible. There will always be multiple computational (and thus ethical) interpretations of a physical system, with no way to figure out what’s “really” happening. No way to figure out if something is suffering or not. No consilience; not now, not ever.

Note: despite apparently granting the point above, Brian also remarks that:

I should add a note on terminology: All computations occur within physics, so any computation is a physical process. Conversely, any physical process proceeds from input conditions to output conditions in a regular manner and so is a computation. Hence, the set of computations equals the set of physical processes, and where I say “computations” in this piece, one could just as well substitute “physical processes” instead.

This seems to be (1) incorrect, for the reasons I give above, or (2) taking substantial poetic license with these terms, or (3) referring to hypercomputation (which might be able to salvage the metaphor, but would invalidate many of FRI’s conclusions dealing with the computability of suffering on conventional hardware).

This objection may seem esoteric or pedantic, but I think it’s important, and that it ripples through FRI’s theoretical framework with disastrous effects.


Objection 7: FRI doesn’t fully bite the bullet on computationalism

Brian suggests that “flavors of computation are flavors of consciousness” and that some computations ‘code’ for suffering. But if we do in fact bite the bullet on this metaphor and place suffering within the realm of computational theory, we need to think in “near mode” and accept all the paradoxes that brings. Scott Aaronson, a noted expert on quantum computing, raises the following objections to functionalism:

I’m guessing that many people in this room side with Dennett, and (not coincidentally, I’d say) also with Everett. I certainly have sympathies in that direction too. In fact, I spent seven or eight years of my life as a Dennett/Everett hardcore believer. But, while I don’t want to talk anyone out of the Dennett/Everett view, I’d like to take you on a tour of what I see as some of the extremely interesting questions that that view leaves unanswered. I’m not talking about “deep questions of meaning,” but about something much more straightforward: what exactly does a computational process have to do to qualify as “conscious”?



There’s this old chestnut, what if each person on earth simulated one neuron of your brain, by passing pieces of paper around. It took them several years just to simulate a single second of your thought processes. Would that bring your subjectivity into being? Would you accept it as a replacement for your current body? If so, then what if your brain were simulated, not neuron-by-neuron, but by a gigantic lookup table? That is, what if there were a huge database, much larger than the observable universe (but let’s not worry about that), that hardwired what your brain’s response was to every sequence of stimuli that your sense-organs could possibly receive. Would that bring about your consciousness? Let’s keep pushing: if it would, would it make a difference if anyone actually consulted the lookup table? Why can’t it bring about your consciousness just by sitting there doing nothing?

To these standard thought experiments, we can add more. Let’s suppose that, purely for error-correction purposes, the computer that’s simulating your brain runs the code three times, and takes the majority vote of the outcomes. Would that bring three “copies” of your consciousness into being? Does it make a difference if the three copies are widely separated in space or time—say, on different planets, or in different centuries? Is it possible that the massive redundancy taking place in your brain right now is bringing multiple copies of you into being?



Maybe my favorite thought experiment along these lines was invented by my former student Andy Drucker.  In the past five years, there’s been a revolution in theoretical cryptography, around something called Fully Homomorphic Encryption (FHE), which was first discovered by Craig Gentry.  What FHE lets you do is to perform arbitrary computations on encrypted data, without ever decrypting the data at any point.  So, to someone with the decryption key, you could be proving theorems, simulating planetary motions, etc.  But to someone without the key, it looks for all the world like you’re just shuffling random strings and producing other random strings as output.


You can probably see where this is going.  What if we homomorphically encrypted a simulation of your brain?  And what if we hid the only copy of the decryption key, let’s say in another galaxy?  Would this computation—which looks to anyone in our galaxy like a reshuffling of gobbledygook—be silently producing your consciousness?


When we consider the possibility of a conscious quantum computer, in some sense we inherit all the previous puzzles about conscious classical computers, but then also add a few new ones.  So, let’s say I run a quantum subroutine that simulates your brain, by applying some unitary transformation U.  But then, of course, I want to “uncompute” to get rid of garbage (and thereby enable interference between different branches), so I apply U-1.  Question: when I apply U-1, does your simulated brain experience the same thoughts and feelings a second time?  Is the second experience “the same as” the first, or does it differ somehow, by virtue of being reversed in time? Or, since U-1U is just a convoluted implementation of the identity function, are there no experiences at all here?


Here’s a better one: many of you have heard of the Vaidman bomb.  This is a famous thought experiment in quantum mechanics where there’s a package, and we’d like to “query” it to find out whether it contains a bomb—but if we query it and there is a bomb, it will explode, killing everyone in the room.  What’s the solution?  Well, suppose we could go into a superposition of querying the bomb and not querying it, with only ε amplitude on querying the bomb, and √(1-ε2) amplitude on not querying it.  And suppose we repeat this over and over—each time, moving ε amplitude onto the “query the bomb” state if there’s no bomb there, but moving ε2 probability onto the “query the bomb” state if there is a bomb (since the explosion decoheres the superposition).  Then after 1/ε repetitions, we’ll have order 1 probability of being in the “query the bomb” state if there’s no bomb.  By contrast, if there is a bomb, then the total probability we’ve ever entered that state is (1/ε)×ε2 = ε.  So, either way, we learn whether there’s a bomb, and the probability that we set the bomb off can be made arbitrarily small.  (Incidentally, this is extremely closely related to how Grover’s algorithm works.)


OK, now how about the Vaidman brain?  We’ve got a quantum subroutine simulating your brain, and we want to ask it a yes-or-no question.  We do so by querying that subroutine with ε amplitude 1/ε times, in such a way that if your answer is “yes,” then we’ve only ever activated the subroutine with total probability ε.  Yet you still manage to communicate your “yes” answer to the outside world.  So, should we say that you were conscious only in the ε fraction of the wavefunction where the simulation happened, or that the entire system was conscious?  (The answer could matter a lot for anthropic purposes.)

To sum up: Brian’s notion that consciousness is the same as computation raises more issues than it solves; in particular, the possibility that if suffering is computable, it may also be uncomputable/reversible, would suggest s-risks aren’t as serious as FRI treats them.

Objection 8: Dangerous combination

Three themes which seem to permeate FRI’s research are:

(1) Suffering is the thing that is bad.

(2) It’s critically important to eliminate badness from the universe.

(3) Suffering is impossible to define objectively, and so we each must define what suffering means for ourselves.

Taken individually, each of these seems reasonable. Pick two, and you’re still okay. Pick all three, though, and you get A Fully General Justification For Anything, based on what is ultimately a subjective/aesthetic call.

Much can be said in FRI’s defense here, and it’s unfair to single them out as risky: in my experience they’ve always brought a very thoughtful, measured, cooperative approach to the table. I would just note that ideas are powerful, and I think theme (3) is especially pernicious if incorrect.

III. QRI’s alternative

Analytic functionalism is essentially a negative hypothesis about consciousness: it’s the argument that there’s no order to be found, no rigor to be had. It obscures this with talk of “function”, which is a red herring it not only doesn’t define, but admits is undefinable. It doesn’t make any positive assertion. Functionalism is skepticism- nothing more, nothing less.

But is it right?

Ultimately, I think these a priori arguments are much like people in the middle ages arguing whether one could ever formalize a Proper System of Alchemy. Such arguments may in many cases hold water, but it’s often difficult to tell good arguments apart from arguments where we’re just cleverly fooling ourselves. In retrospect, the best way to *prove* systematized alchemy was possible was to just go out and *do* it, and invent Chemistry. That’s how I see what we’re doing at QRI with Qualia Formalism: we’re assuming it’s possible to build stuff, and we’re working on building the object-level stuff.

What we’ve built with QRI’s framework

Note: this is a brief, surface-level tour of our research; it will probably be confusing for readers who haven’t dug into our stuff before. Consider this a down-payment on a more substantial introduction.

My most notable work is Principia Qualia, in which I lay out my meta-framework for consciousness (a flavor of dual-aspect monism, with a focus on Qualia Formalism) and put forth the Symmetry Theory of Valence (STV). Essentially, the STV is an argument that much of the apparent complexity of emotional valence is evolutionarily contingent, and if we consider a mathematical object isomorphic to a phenomenological experience, the mathematical property which corresponds to how pleasant it is to be that experience is the object’s symmetry. This implies a bunch of testable predictions and reinterpretations of things like what ‘pleasure centers’ do (Section XI; Section XII). Building on this, I offer the Symmetry Theory of Homeostatic Regulation, which suggests understanding the structure of qualia will translate into knowledge about the structure of human intelligence, and I briefly touch on the idea of Neuroacoustics.

Likewise, my colleague Andrés Gómez Emilsson has written about the likely mathematics of phenomenology, including The Hyperbolic Geometry of DMT Experiences, Tyranny of the Intentional Object, and Algorithmic Reduction of Psychedelic States. If I had to suggest one thing to read in all of these links, though, it would be the transcript of his recent talk on Quantifying Bliss, which lays out the world’s first method to objectively measure valence from first principles (via fMRI) using Selen Atasoy’s Connectome Harmonics framework, the Symmetry Theory of Valence, and Andrés’s CDNS model of experience.

These are risky predictions and we don’t yet know if they’re right, but we’re confident that if there is some elegant structure intrinsic to consciousness, as there is in many other parts of the natural world, these are the right kind of risks to take.

I mention all this because I think analytic functionalism- which is to say radical skepticism/eliminativism, the metaphysics of last resort- only looks as good as it does because nobody’s been building out any alternatives.

IV. Closing thoughts

FRI is pursuing a certain research agenda, and QRI is pursuing another, and there’s lots of value in independent explorations of the nature of suffering. I’m glad FRI exists, everybody I’ve interacted with at FRI has been great, I’m happy they’re focusing on s-risks, and I look forward to seeing what they produce in the future.

On the other hand, I worry that nobody’s pushing back on FRI’s metaphysics, which seem to unavoidably lead to the intractable problems I describe above. FRI seems to believe these problems are part of the territory, unavoidable messes that we just have to make philosophical peace with. But I think that functionalism is a bad map, that the metaphysical messes it leads to are much worse than most people realize (fatal to FRI’s mission), and there are other options that avoid these problems (which, to be fair, is not to say they have no problems).

Ultimately, FRI doesn’t owe me a defense of their position. But if they’re open to suggestions on what it would take to convince a skeptic like me that their brand of functionalism is viable, or at least rescuable, I’d offer the following:

Re: Objection 1 (motte-and-bailey), I suggest FRI should be as clear and complete as possible in their basic definition of suffering. In which particular ways is it ineffable/fuzzy, and in which particular ways is it precise? What can we definitely say about suffering, and what can we definitely never determine? Preregistering ontological commitments and methodological possibilities would help guard against FRI’s definition of suffering changing based on context.

Re: Objection 2 (intuition duels), FRI may want to internally “war game” various future scenarios involving AGI, WBE, etc, with one side arguing that a given synthetic (or even extraterrestrial) organism is suffering, and the other side arguing that it isn’t. I’d expect this would help diagnose what sorts of disagreements future theories of suffering will need to adjudicate, and perhaps illuminate implicit ethical intuitions. Sharing the results of these simulated disagreements would also be helpful in making FRI’s reasoning less opaque to outsiders, although making everything transparent could lead to certain strategic disadvantages.

Re: Objection 3 (convergence requires common truth), I’d like FRI to explore exactly what might drive consilience/convergence in theories of suffering, and what precisely makes one theory of suffering better than another, and ideally to evaluate a range of example theories of suffering under these criteria.

Re: Objection 4 (assuming that consciousness is a reification produces more confusion, not less), I would love to see a historical treatment of reification: lists of reifications which were later dissolved (e.g., élan vital), vs scattered phenomena that were later unified (e.g., electromagnetism). What patterns do the former have, vs the latter, and why might consciousness fit one of these buckets better than the other?

Re: Objection 5 (the Hard Problem of Consciousness is a red herring), I’d like to see a more detailed treatment of what kinds of problem people have interpreted the Hard Problem as, and also more analysis on the prospects of Qualia Formalism (which I think is the maximally-empirical, maximally-charitable interpretation of the Hard Problem). It would be helpful for us, in particular, if FRI preregistered their expectations about QRI’s predictions, and their view of the relative evidence strength of each of our predictions.

Re: Objection 6 (mapping to reality), this is perhaps the heart of most of our disagreement. From Brian’s quotes, he seems split on this issue; I’d like clarification about whether he believes we can ever precisely/objectively map specific computations to specific physical systems, and vice-versa. And if so— how? If not, this seems to propagate through FRI’s ethical framework in a disastrous way, since anyone can argue that any physical system does, or does not, ‘code’ for massive suffering, and there’s no principled way to derive any ‘ground truth’ or even pick between interpretations in a principled way (e.g. my popcorn example). If this isn’t the case— why not?

Brian has suggested that “certain high-level interpretations of physical systems are more ‘natural’ and useful than others” (personal communication); I agree, and would encourage FRI to explore systematizing this.

It would be non-trivial to port FRI’s theories and computational intuitions to the framework of “hypercomputation”– i.e., the understanding that there’s a formal hierarchy of computational systems, and that Turing machines are only one level of many– but it may have benefits too. Namely, it might be the only way they could avoid Objection 6 (which I think is a fatal objection) while still allowing them to speak about computation & consciousness in the same breath. I think FRI should look at this and see if it makes sense to them.

Re: Objection 7 (FRI doesn’t fully bite the bullet on computationalism), I’d like to see responses to Aaronson’s aforementioned thought experiments.

Re: Objection 8 (dangerous combination), I’d like to see a clarification about why my interpretation is unreasonable (as it very well may be!).


In conclusion- I think FRI has a critically important goal- reduction of suffering & s-risk. However, I also think FRI has painted itself into a corner by explicitly disallowing a clear, disagreement-mediating definition for what these things are. I look forward to further work in this field.


Mike Johnson

Qualia Research Institute

Acknowledgements: thanks to Andrés Gómez Emilsson, Brian Tomasik, and Max Daniel for reviewing earlier drafts of this.


My sources for FRI’s views on consciousness:
Flavors of Computation are Flavors of Consciousness:
Is There a Hard Problem of Consciousness?
Consciousness Is a Process, Not a Moment
How to Interpret a Physical System as a Mind
Dissolving Confusion about Consciousness
Debate between Brian & Mike on consciousness:
Max Daniel’s EA Global Boston 2017 talk on s-risks:
Multipolar debate between Eliezer Yudkowsky and various rationalists about animal suffering:
The Internet Encyclopedia of Philosophy on functionalism:
Gordon McCabe on why computation doesn’t map to physics:
Toby Ord on hypercomputation, and how it differs from Turing’s work:
Luke Muehlhauser’s OpenPhil-funded report on consciousness and moral patienthood:
Scott Aaronson’s thought experiments on computationalism:
Selen Atasoy on Connectome Harmonics, a new way to understand brain activity:
My work on formalizing phenomenology:
My meta-framework for consciousness, including the Symmetry Theory of Valence:
My hypothesis of homeostatic regulation, which touches on why we seek out pleasure:
My exploration & parametrization of the ‘neuroacoustics’ metaphor suggested by Atasoy’s work:
My colleague Andrés’s work on formalizing phenomenology:
A model of DMT-trip-as-hyperbolic-experience:
June 2017 talk at Consciousness Hacking, describing a theory and experiment to predict people’s valence from fMRI data:
A parametrization of various psychedelic states as operators in qualia space:
A brief post on valence and the fundamental attribution error:
A summary of some of Selen Atasoy’s current work on Connectome Harmonics: