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.

Californidine

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

Californidine and MDMA

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

Notable Leads for Great Drug Combos

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Entry on MDPR, from PIHKAL)

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

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

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

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

LSD + DMT Visual Replication

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

Try it yourself: 50Hz to 500Hz with 100Hz base, and 100Hz to 1000Hz with 400Hz base.

Idiosyncratic Responses

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

Drug Cocktails From First Principles

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

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

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

True for both people and drugs!

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

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

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

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

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

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

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 “npK_i“, 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).