Making Amazing Recreational Drug Cocktails

Californidine

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

1200px-Californidine.svg

Californidine

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

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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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Entry on MDPR, from PIHKAL)

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

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

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

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

NO-MISMATCH-PATTERN

LSD + DMT Visual Replication

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

Idiosyncratic Responses

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

Drug Cocktails From First Principles

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

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

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

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True for both people and drugs!

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

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

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

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

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

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

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

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

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

Master Druggist (Synapse? Dendrite?)

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

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

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

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



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

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

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

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

(source)

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

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


“Dirty” Maintenance

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

Coffee Saves Lives

[July 18 2019 addendum: This assumes that coffee has a causal- rather than merely correlational- influence on longevity. See comment section for more details.]


The T-shirt in the featured image was probably designed as a joke, but I take it very seriously.

Indeed, I think there is a strong case to be made that subsidizing coffee could be seen as an Effective Altruist priority. You see, you can save a life with coffee for as little as $50k. This makes coffee an intervention that is on par with some of the top charities in the world, and it is an outlier when it comes to the cost-benefit ratio of medical interventions. Consider how, e.g. this article on QALY states that:

“The UK’s recommendations, for example, are about £20,000 to £30,000 ($30,000 to $45,000) for each additional year of good health, once it has been adjusted to take into account the quality of life. So a drug that achieved 0.5 on the QALY measure would only merit £10,000-15,000 ($15,000 to $22,500).”

Assuming a QALY-adjusted average life-span of about 60 years per person, coffee is about 30 to 50 times more cost-effective than the types of medical interventions the UK is willing to subsidize to extend people’s lives. And that’s not even considering what people themselves are willing to pay to extend their own lives, which is, of course, a lot more than what a government would.

Relative to GiveWell‘s top charities this is still not the best intervention out there (with some of the ultra-effective charities saving a life for about 2,000 dollars). I would nonetheless point out that the ultra-effective charities out there are all effective because they address populations where very basic human needs are not typically met. In Malaria-ridden, war-torn areas, a little can go a long way. But what’s different about coffee is that it is as effective everywhere in the world. Sure, you can save a life with $50k in many African countries. But can you do so in Sweden?! With coffee you can!

Anyhow, how did I arrive at these numbers? Well consider that you can get about 380 doses of coffee for as little as 10 dollars.*

So this means you can have a cup of coffee for as little as 2.63 cents(!). In turn, we know from a lot of research that each cup of coffee up to 4 cups a day prevents about 1/2 micromorts (interestingly, it is just as cost-effective to encourage people who don’t drink coffee to drink 1 cup as it would be to encourage people who drink 3 to go ahead and drink 4).

Given those numbers, we have that the cost of a full life-span worth of micromorts is about $52,631.58.

Why are we not funding this?!


*With: Example 48 oz brand. (we could do even better buying in bulk – I reached out to a delivery company to get a quota and will update when I know more).

Low-Dose Ibogaine for Hedonic Tone Augmentation

Excerpt from Tools of Titans (ps. 119-120) by Tim Ferriss (2017)

Biochemically, Why Is Ibogaine So Oddly Effective?

“[Ibogaine isn’t] just masking the withdrawal like a substitution drug would. For example, if somebody on heroin takes methadone, they won’t have withdrawal for a period of time, but as soon as the methadone leaves the system, the withdrawal comes back. This is not something that happens on ibogaine. You take ibogaine, and the withdrawal is gone – 90% of the withdrawal is completely gone. That’s telling us that the ibogaine is actually changing the receptor to the way it was before the person started using. It’s actually restructuring and healing it. Ibogaine appears to affect almost every major class of neurotransmitter, primarily via NMDA, serotonin, sigma, and nicotinic receptors. A prominent ibogaine researcher, Dr. Kenneth Alper [of New York University School of Medicine], has stated in presentations that certain aspects of ibogaine defy traditional paradigms in pharmacology.”

Tim Ferriss: “I have noticed that microdosing seemed to increase my happiness ‘set point’ by 5 to 10%, to peg a number on my subjective experience. This persists for several days after consumption. Preliminarily, the effect appears to relate to up-regulation of mu-opioid receptors. From one study: ‘…in vivo evidence has been provided for the possible interaction of ibogaine with μ-opioid receptor following its metabolism to noribogaine.’*”

Martin: “[In treating chemical dependency] it’s opiate-specific. We have seen some benefits for certain psychiatric medications, but not for benzodiazepine or alcohol withdrawal. These two withdrawals are actually dangerous. When somebody gets the shakes, it’s DT (delirium tremens) and that can be deadly. So, it’s a very delicate process and somebody who’s physically addicted to alcohol should not take ibogaine. They need to detox first, and then they can take ibogaine for the psychological and the anti-addictive benefits.”


* Bhargava, Hemendra N., Ying-Jun Cao, and Guo-Min Zhao. “Effects of ibogaine and noribogaine on the antinociceptive action of μ-, δ-, and κ-opioid receptor agonists in mice.” Brain research 752, no. 1 (1997): 234-238


See also: Anti-Tolerance Drugs, On Hitting the Actual Target of Hedonic Tone, and A Novel Approach to Detoxification from Methadone Using Low, Repeated, and Cumulative Administering of Ibogaine (from Psychedelic Science 2017).

On Hitting the Actual Target of Hedonic Tone

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

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

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

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

imgsrv

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


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

Cooling It Down To Partying It Up

A relatively recent hypothesis for the neurotoxicity associated with MDMA is that it causes the brain to over-heat (see: 1, 2, 3). This would make the sorts of environments in which people take it particularly hazardous (hot raves, nightclubs, warm baths, and wild sex).

I really hope this is the core main reason for MDMA’s long-term deleterious effects.

Why?

Because then the damage would be completely preventable! In particular, I would point you to the athletic performance-enhancing technology developed at Stanford in 2012 that uses rapid thermal exchange devices (aka. “the cooling glove”*) in order to cool your blood and allow you to compete at a higher level. This is an extremely efficient method to keep the temperature of your whole body (including your brain!) within a healthy range.

Sadly, the device is likely to get banned for athletic purposes (it would be, some say, an unfair advantage if some teams have access to the cooling glove and others don’t). Sports are, of course, completely inconsequential, so the fact that the device is likely to get banned for this application shouldn’t matter. Yet it does, because as a result many people seem to be losing interest in this line of research.

Maybe, I would posit, the device could be resurrected as part of a modern harm-reduction strategy. Imagine night-clubs with a chill-out space stocked with dozens of cooling gloves. Party for 30 minutes, cool down for 10 minutes, repeat. If this could allow people to take MDMA once every month for the rest of their lives without enduring the brain damage that doing this usually causes… wouldn’t that be wonderful? I would expect it to also be highly beneficial for the benevolence of culture and the overall mental health of our society.

And this is all to say: Who would have known… that “being cool” was the key to partying for the rest of your life? Cool it down and party it up!


*For a skeptical take on the device, see: Better Than Steroids? The hype behind Stanford’s magic “cooling glove” for athletes. And a comeback article that extends its use to more serious applications: Cooling glove developed by Stanford researchers helps athletes and patients.

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

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

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

– David Pearce, in The 3 Supers

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

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

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

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

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

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

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

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

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

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


Bonus Content: What About Us?

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

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

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

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

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

Ozzy Osbourne’s Genome (Scientific American, 2010)

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

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

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


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

Featured image credit: source.

Anti-Tolerance Drugs

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

 

Future Opioids, by David Pearce

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

 

– Still Life with Woodpecker by Tom Robbins

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

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

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

Tier System

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

Opioid System

Tier 1

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

Tier 2

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

Tier 3

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

Tier 4

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

Tier 5

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

 

GABA System

Tier 1

  1. Flumazenil (note: very dose-dependent)

Tier 2

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

Tier 3

  1. Dihydromyricetin

See also.

Dopamine System

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

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

See also.


Tanks to Adam Karlovsky for help compiling these lists.

Connectome-Specific Harmonic Waves on LSD

The harmonics-in-connectome approach to modeling brain activity is a fascinating paradigm. I am privileged to have been at this talk in the 2017 Psychedelic Science conference. I’m extremely happy find out that MAPS already uploaded the talks. Dive in!

Below is a partial transcript of the talk. I figured that I should get it in written form in order to be able to reference it in future articles. Enjoy!

[After a brief introduction about harmonic waves in many different kinds of systems… at 7:04, Selen Atasoy]:

We applied the [principle of harmonic decomposition] to the anatomy of the brain. We made them connectome-specific. So first of all, what do I mean by the human connectome? Today thanks to the recent developments in structural neuroimaging techniques such as diffusion tensor imaging, we can trace the long-distance white matter connections in the brain. These long-distance white matter fibers (as you see in the image) connect distant parts of the brain, distant parts of the cortex. And the set of all of the different connections is called the connectome.

selen_connectome_image

Now, because we know the equation governing these harmonic waves, we can extend this principle to the human brain by simply solving the same equation on the human connectome instead of a metal plate (Chladni plates) or the anatomy of the zebra. And if you do that, we get a set of harmonic patterns, this time emerging in the cortex. And we decided to call these harmonic patterns connectome harmincs. And each of these connectome harmonic patterns are associated with a different frequency. And because they correspond to different frequencies they are all independent, and together they give you a new language, so to speak, to describe neural activity. So in the same way the harmonic patterns are building blocks of these complex patterns we see on animal coats, these connectome harmonics are the building blocks of the complex spatio-temporal patterns of neural activity.

Describing and explaining neural activity by using these connectome harmonics as brain states is really not very different than decomposing a complex musical pieces into its musical notes. It’s simply a new way of representing your data, or a new language to express it.

What is the advantage of using this new language? So why not use the state-of-the-art conventional neurimaging analysis methods? Because these connectome harmonics, by definition are the vibration modes, but applied to the anatomy of the human brain, and if you use them as brain states to express neural activity we can compute certain fundamental principles very easily such as the energy or the power.

The power would be the strength of activation of each of these states in neural activity. So how strongly that particular state contributes to neural activity. And the energy would be a combination of this strength of activation with the intrinsic energy of that particular brain state, and the intrinsic energy comes from the frequency of its vibration (in the analogy of vibration).

So in this study we looked at the power and the energy of these connectome harmonic brain states in order to explore the neural correlates of the LSD experience.

We looked at 12 healthy participants who received either 75µg of LSD (IV) or a placebo, over two sessions. These two sessions were 14 days apart in counter-balanced order. And the fMRI scans consisted of 3 eyes-closed resting states scans, each lasting 7 minutes, in the first and the third scan the participants were simply resting, eyes closed, but in the second scan they were also listening to music. And after each scan, the participants rated the intensity of certain experiences.

activity_power_energy_scans.png

So if you look at, firstly, at the total power and the total energy of each of these scans under LSD and placebo, what we see is that under LSD both the power as well as the energy of brain activity increases significantly.

And if we compute the probability of observing a certain energy value on LSD or placebo, what we see is that the peak of this probability distribution clearly shoots towards high energy values under LSD.

energy_difference

And that peak is even slightly higher in terms of probability when the subjects were listening to music. So if we interpret that peak as, in a way, the characteristic energy of a state, you can see that it shifts towards higher energy under LSD, and that this effect is intensified when listening to music.

And then we asked, which of these brain states, which of these frequencies, were actually contributing to this energy increase. So we partitioned the spectrum of all of these harmonic brain states into different parts and computed the energy of each of these partitions individually. So in total we have around 20,000 brain states. And if you look at the energy differences in LSD and placebo, what we find is that for a very narrow range of low frequencies actually these brain states were decreasing their energy on LSD. But for a very broad range of high frequencies, LSD was inducing an energy increase. So this says that LSD alters brain dynamics in a very frequency-selective manner. And it was causing high frequencies to increase their energy.

So next we looked at whether these changes we are observing in brain activity are correlated with any of the experiences that the participants themselves were having in that moment. If you look at the energy changes within the narrow range of low frequencies, we found that the energy changes in that range significantly correlated with the intensity of the experience of ego dissolution. The loss of subjective self.

ego_dissolution

And very interestingly, the same range of energy change within the same frequency range also significantly correlated with the intensity of emotional arousal, whether the experience was positive or negative. This could be quite relevant for studies looking into potential therapeutic applications of LSD.

emotional_arousal

Next, when we look at a slightly higher range of frequencies, what we found was that the energy changes within that range significantly correlated with the positive mood.

higher_frequencies

In brief, this suggests that it’s rather the low frequency brain states which correlated with ego dissolution or with emotional arousal, and it’s the activity of higher frequencies that is correlated with the positive experiences.

Next, we wanted to check the size of the repertoire of active brain states. And if you look at the probability of activation for any brain state (so we are not distinguishing for any frequency brain states), what we observe is that the probability of a brain state being silent (zero contribution), actually decreased under LSD. And the probability of a brain state contributing very strongly, which corresponds to the tails of these distributions, were increased under LSD. So this suggests that LSD was activating more brain states simultaneously.

repertoaire

And if we go back to the music analogy that we used in the beginning, that would correspond to playing more musical notes at the same time. And it’s very interesting, because studies that have looked at improvising, those who have looked at jazz improvisation, show that improvising jazz musicians play significantly more musical notes compared to memorized play. And this is what we seem to be finding under the effect of LSD. That your brain is actually activating more of these brain states simultaneously.

cross-frequency

And it does so in a very non-random fashion. So if you look at the correlation across different frequencies. Like at the co-activation patterns, and their activation over time. You may interpret it as the “communication across various frequencies”. What we found is that for a very broad range of the spectrum, there was a higher correlation across different frequencies in their activation patterns under LSD compared to placebo.

So this really says that LSD is actually causing a reorganization, rather than a random activation of brain states. It’s expanding the repertoire of active brain states, while maintaining -or maybe better said- recreating a complex but spontaneous order. And in the musical analogy it’s really very similar to jazz improvisation, to think about it in an intuitive way.

Now, there is actually one particular situation when dynamical systems such as the brain, and systems that change their activity over time, show this type of emergence of complex order, or enhanced improvisation, enhanced repertoire of active states. And this is when they approach what is called criticality. Now, criticality is this special type of behavior, special type of dynamics, that emerges right at the transition between order and chaos. When these two (extreme) types of dynamics are in balance. And criticality is said to be “the constantly shifting battle zone between stagnation and anarchy. The one place where a complex system can be spontaneous, adaptive, and alive” (Waldrop 1992). So if a system is approaching criticality, there are very characteristic signatures that you would observed in the data, in the relationships that you plot in your data.

And one of them is -and probably the most characteristic of them- is the emergence of power laws. So what does that mean? If you plot one observable in our data, which for example, in our case would be the maximum power of a brain state, in relationship to another observable, for example, the wavenumber, or the frequency of that brain state, and you plot them in logarithmic coordinates, that would mean that if they follow power laws, they would approximate a line. And this is exactly what we observe in our data, and surprisingly for both LSD as well as for placebo, but with one very significant and remarkable difference: because the high frequencies increase their power on LSD, this distribution follows this power law, this line, way more accurately under LSD compared to placebo. And here you see the error of the fit, which is decreasing.

This suggests that LSD shoots brain dynamics further towards criticality.  The signature of criticality that we find in LSD and in placebo is way more enhanced, way more pronounced, under the effect of LSD. And we found the same effect, not only for the maximum power, but also for the mean power, as well as for the power of fluctuations.

criticality_signature

So this suggests that the criticality actually may be the principle that is underlying this emergence of complex order, and this reorganization of brain dynamics, and which leads to enhanced improvisation in brain activity.

So, to summarize briefly, what we found was that LSD increases the total power as well as total energy of brain activity. It selectively activates high frequency brain states, and it expands the repertoire or active brain states in a very non-random fashion. And the principle underlying all of these changes seems to be a reorganization of brain dynamics, right at criticality, right at the edge of chaos, or just as the balance between order and chaos. And very interestingly, the “edge of chaos”, or the edge of criticality, is said to be where “life has enough stability to sustain itself, and enough creativity to deserve the name of life” (Waldrop 1992). So I leave you with that, and thank you for your attention.

[Applauses; ends at 22:00, followed by Q&A]

ELI5 “The Hyperbolic Geometry of DMT Experiences”

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I wrote the following in response to a comment on the r/RationalPsychonaut subreddit about this DMT article I wrote some time ago. The comment in question was: “Can somebody eli5 [explain like I am 5 years old] this for me?” So here is my attempt (more like “eli12”, but anyways):

In order to explain the core idea of the article I need to convey the main takeaways of the following four things:

  1. Differential geometry,
  2. How it relates to symmetry,
  3. How it applies to experience, and
  4. How the effects of DMT turn out to be explained (in part) by changes in the curvature of one’s experience of space (what we call “phenomenal space”).

1) Differential Geometry

If you are an ant on a ball, it may seem like you live on a “flat surface”. However, let’s imagine you do the following: You advance one centimeter in one direction, you turn 90 degrees and walk another centimeter, turn 90 degrees again and advance yet another centimeter. Logically, you just “traced three edges of a square” so you cannot be in the same place from which you departed. But let’s says that you somehow do happen to arrive at the same place. What happened? Well, it turns out the world in which you are walking is not quite flat! It’s very flat from your point of view, but overall it is a sphere! So you ARE able to walk along a triangle that happens to have three 90 degree corners.

That’s what we call a “positively curved space”. There the angles of triangles add up to more than 180 degrees. In flat spaces they add up to 180. And in “negatively curved spaces” (i.e. “negative Gaussian curvature” as talked about in the article) they add up to less than 180 degrees.

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Eight 90-degree triangles on the surface of a sphere

So let’s go back to the ant again. Now imagine that you are walking on some surface that, again, looks flat from your restricted point of view. You walk one centimeter, then turn 90 degrees, then walk another, turn 90 degrees, etc. for a total of, say, 5 times. And somehow you arrive at the same point! So now you traced a pentagon with 90 degree corners. How is that possible? The answer is that you are now in a “negatively curved space”, a kind of surface that in mathematics is called “hyperbolic”. Of course it sounds impossible that this could happen in real life. But the truth is that there are many hyperbolic surfaces that you can encounter in your daily life. Just to give an example, kale is a highly hyperbolic 2D surface (“H2” for short). It’s crumbly and very curved. So an ant might actually be able to walk along a regular pentagon with 90-degree corners if it’s walking on kale (cf. Too Many Triangles).

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An ant walking on kale may infer that the world is an H2 space.

In brief, hyperbolic geometry is the study of spaces that have this quality of negative curvature. Now, how is this related to symmetry?

2) How it relates to symmetry

As mentioned, on the surface of a sphere you can find triangles with 90 degree corners. In fact, you can partition the surface of a sphere into 8 regular triangles, each with 90 degree corners. Now, there are also other ways of partitioning the surface of a sphere with regular shapes (“regular” in the sense that every edge has the same length, and every corner has the same angle). But the number of ways to do it is not infinite. After all, there’s only a handful of regular polyhedra (which, when “inflated”, are equivalent to the ways of partitioning the surface of a sphere in regular ways).

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If you instead want to partition a plane in a regular way with geometric shapes, you don’t have many options. You can partition it using triangles, squares, and hexagons. And in all of those cases, the angles on each of the vertices will add up to 360 degrees (e.g. six triangles, four squares, or thee corners of hexagons meeting at a point). I won’t get into Wallpaper groups, but suffice it to say that there are also a limited number of ways of breaking down a flat surface using symmetry elements (such as reflections, rotations, etc.).

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Regular tilings of 2D flat space

Hyperbolic 2D surfaces can be partitioned in regular ways in an infinite number of ways! This is because we no longer have the constraints imposed by flat (or spherical) geometries where the angles of shapes must add up to a certain number of degrees. As mentioned, in hyperbolic surfaces the corners of triangles add up to less than 180 degrees, so you can fit more than 6 corners of equilateral triangles at one point (and depending on the curvature of the space, you can fit up to an infinite number of them). Likewise, you can tessellate the entire hyperbolic plane with heptagons.

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Hyperbolic tiling: Each of the heptagons is just as big (i.e. this is a projection of the real thing)

On the flip side, if you see a regular partitioning of a surface, you can infer what its curvature is! For example, if you see that a surface is entirely covered with heptagons, three on each of the corners, you can be sure that you are seeing a hyperbolic surface. And if you see a surface covered with triangles such that there are only four triangles on each joint, then you know you are seeing a spherical surface. So if you train yourself to notice and count these properties in regular patterns, you will indirectly also be able to determine whether the patterns inhabit a spherical, flat, or hyperbolic space!

3) How it applies to experience

How does this apply to experience? Well, in sober states of consciousness one is usually restricted to seeing and imagining spherical and flat surfaces (and their corresponding symmetric partitions). One can of course look at a piece of kale and think “wow, that’s a hyperbolic surface” but what is impossible to do is to see it “as if it were flat”. One can only see hyperbolic surfaces as projections (i.e. where we make regular shapes look irregular so that they can fit on a flat surface) or we end up contorting the surface in a crumbly fashion in order to fit it in our flat experiential space. (Note: even sober phenomenal space happens to be based on projective geometry; but let’s not go there for now.)

4) DMT: Hyperbolizing Phenomenal Space

In psychedelic states it is common to experience whatever one looks at (or, with more stunning effects, whatever one hallucinates in a sensorially-deprived environment such as a flotation tank) as slowly becoming more and more symmetric. Symmetrical patterns are attractors in psychedelia. It’s common for people to describe their acid experiences as “a kaleidoscope of colors and meaning”. We should not be too quick to dismiss these descriptions as purely metaphorical. As you can see from the article Algorithmic Reduction of Psychedelic States as well as PsychonautWiki’s Symmetrical Texture Repetition, LSD and other psychedelics do in fact “symmetrify” the textures you experience!

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What gravel might look like on 150 mics of LSD (Source)

As it turns out, this symmetrification process (what we call “lowering the symmetry detection/propagation threshold”) does allow one to experience any of the possible ways of breaking down spherical and flat surfaces in regular ways (in addition to also enabling the experience of any wallpaper group!). Thus the surfaces of the objects one hallucinates on LSD (specially for Closed Eyes Visuals), are usually carpeted with patterns that have either spherical or flat symmetries (e.g. seeing honeycombs, square grids, regular triangulations, etc.; or seeing dodecahedra, cubes, etc.).

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17 wallpaper symmetry groups

Only on very high doses of classic psychedelics does one start to experience objects that have hyperbolic curvature. And this is where DMT becomes very relevant. Vaping it is one of the most efficient ways of achieving “unworldly levels of psychedelia”:

On DMT the “symmetry detection threshold” is reduced to such an extent that any surface you look at very quickly gets super-saturated with regular patterns. Since (for reasons we don’t understand) our brain tries to incorporate whatever shape you hallucinate into the scene as part of the scene, the result of seeing too many triangles (or heptagons, or whatever) is that your brain will “push them into the surfaces” and, in effect, turn those surfaces into hyperbolic spaces.HeptagonsIndrasPearls

Yet another part of your brain (or system of consciousness, whatever it turns out to be) recognizes that “wait, this is waaaay too curved somehow, let me try to shape it into something that could actually exist in my universe”. Hence, in practice, if you take between 10 and 20 mg of DMT, the hyperbolic surfaces you see will become bent and contorted (similar to the pictures you find in the article) just so that they can be “embedded” (a term that roughly means “to fit some object into a space without distorting its properties too much”) into your experience of the space around you.

But then there’s a critical point at which this is no longer possible: Even the most contorted embeddings of the hyperbolic surfaces you experience cannot fit any longer in your normal experience of space on doses above 20 mg, so your mind has no other choice but to change the curvature of the 3D space around you! Thus when you go from “very high on DMT” to “super high on DMT” it feels like you are traveling to an entirely new dimension, where the objects you experience do not fit any longer into the normal world of human experience. They exist in H3 (hyperbolic 3D space). And this is in part why it is so extremely difficult to convey the subjective quality of these experiences. One needs to invoke mathematical notions that are unfamiliar to most people; and even then, when they do understand the math, the raw feeling of changing the damn geometry of your experience is still a lot weirder than you could ever anticipate.

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Anybody else want to play hyperbolic soccer? Humans vs. Entities, the match of the eon!

Note: The original article goes into more depth

Now that you understand the gist of the original article, I encourage you to take a closer look at it, as it includes content that I didn’t touch in this ELI5 (or 12) summary. It provides a granular description of the 6 levels of DMT experience (Threshold, Chrysanthemum, Magic Eye, Waiting Room, Breakthrough, and Amnesia), many pictures to illustrate the various levels as well as the particular emergent geometries, and a theoretical discussion of the various algorithmic reductions that might explain how the hyperbolization of phenomenal space takes place based on combining a series of simpler effects together.