Buddhist Annealing: Wireheading Done Right with the Seven Factors of Awakening (link)
This video discusses the connections between meditative flow (any feeling of change) and the two QRI paradigms of “Wireheading Done Right” and “Neural Annealing”. To do so, I explore how each of the “seven factors of awakening” can be interpreted as operations that you do to flow. In a nutshell: the factors are “energy management techniques”, which when used in the right sequences and dosages, tend to result in wholesome neural annealing.
I then go on to discuss two fascinating dualities: (1) The dual relationship between standing wave patterns and vibratory frequencies. And (2) the dual correspondence between annealing at the computational level (REBUS) and annealing in resonance networks.
(1) Describes how the crazy patterns that come out of meditation and psychedelics are not irrelevant. They are, in a way, the dual counterpart to the emotional processing that you are undergoing. Hence why ugly emotions manifest as discordant structures whereas blissful feelings come together with beautiful geometries.
(2) Articulates how simulated annealing methods in probabilistic graphical models such as those that underlie the synthesis of entropic disintegration and the free energy principle (Friston’s and Carhart-Harris’ REBUS model) describe belief updating. Whereas annealing at the implementation level refers to a dissonance-minimization technique in resonance networks. In turn, if these are “two sides of the same coin”, we can expect to find that operations in one domain will translate to operations in the other domain. In particular, I discuss how resisting information (“denial”, “cognitive dissonance”) has a corresponding subjective texture associated with muscle tension, “resistance”, viscosity, and hardness. Equanimity, in turn, allows the propagation of both waves of dissonance, consonance, and noise as well as bundles of information. This has major implications for how to maximize the therapeutic benefit of psychedelics.
Finally, I explain how we could start formalizing Shinzen Young’s observation that you can, not only “read the contents of your subconscious”, but indeed also “heal your subconscious by greeting it with enough concentration, clarity, and equanimity”. Negentropy in the resonance network (patches of highly-ordered “combed” coherent resonance across levels of the hierarchy) can be used to heal patches of dissonance. This is why clean high-valence meditative objects (e.g. metta) can absorb and dissipate the internal dissonance stored in patterns of habitual responses. In turn, this might ultimately allow us to explain why, speaking poetically, it is true that love can heal all wounds. 🙂
~Qualia of the Day: Nirvana Rose~
(Skip to ~10:00 if you don’t need a recap of Wireheading Done Right and Neural Annealing)
[ps. correction – I wrote a 30 page document about my retreat, not a 50 word document]
Neural Correlates of the DMT Experience Assessed with Multivariate EEG (Christopher Timmermann, Leor Roseman, Michael Schartner, Raphael Milliere, Luke T. J. Williams, David Erritzoe, Suresh Muthukumaraswamy, Michael Ashton, Adam Bendrioua, Okdeep Kaur, Samuel Turton, Matthew M. Nour, Camilla M. Day, Robert Leech, David J. Nutt & Robin L. Carhart-Harris)
The Purple Pill: What Happens When You Take the Blue and the Red Pill at the Same Time? (link)
“The Purple Pill is the pill that gives you both high hedonic tone and an unprejudiced open-ended approach to the pursuit of truth. For losing truth is to lose it all, but to lose it all is only bad because it makes you and others suffer in the wider universe.” – The Purple Pill (Qualia Computing)
In this talk I explain that the “Blue vs. Red Pill” trope relies on a false dichotomy. You don’t need to choose between depressive realism and comforting illusions. Put differently, you don’t need to choose between truth and happiness. High hedonic tone is not incompatible with one’s representational accuracy of causal structures. The world, and the existence of experiential heaven and hell, can be understood without curling into a ball and crying your way to sleep. More so, effective and persistent action towards the good requires that you don’t believe in this false dichotomy, for sustainable altruistic productivity necessitates both accurate models and positive motivations. Thus, the aspiring paradise engineer ought to be willing to take the Purple Pill to move onwards.
I advocate having a balanced portfolio of (1) efforts to minimize experiential hell, (2) techniques to increase the hedonic baseline sustainably, and (3) methods to reliably experience peak states of consciousness in a sane way.
I do not think that spending 100% of one’s time in “destroying hell” is a sustainable approach to life because it does not allow you to “reinvest” in the conditions that gave rise to one’s goodness to begin with (otherwise you become more of a martyr than an effective player in the field!). More so, the relationship between suffering and productivity is non-trivial, which means that to just helping people who suffer extremely does not generally pay off in terms of productive action towards the cause in the future. Hence, improving baseline is just as important: it is precisely what allows people to go from near zero productivity to a high level of productivity. Finally, the benefits of having access to reliable, pro-social ultra-blissful states of consciousness should not be underestimated. They are an important piece of the puzzle because they motivate the “animal self” and are deeply reassuring. Thus, as a “package”, I see a lot of potential in simultaneously reducing negative extremes, improving the baseline, and achieving new heights of bliss. This, to me, is what I see as the path forward.
Topics I cover span: Trungpa’s “Spiritual Materialism” (the attitude of using exalted states of consciousness to “decorate our ego”), optimization problems/reinvesting in the good, sane in-group/out-group dynamics, the game theory of virtue signaling, and the importance of having an explicit commitment to the wellbeing of all sentient beings (to prevent value drift).
What are the differences between DMT and 5-MeO-DMT? And what gives rise to those differences? In this video we discuss 12 different ways to analyze the strange and unique effects of these substances. We go over the 9 lenses already discussed in Qualia Computing* and add three more.
Starting with three new lenses (5-MeO-DMT left/DMT right):
A) Global Coherence vs. Competing Clusters of Coherence: 5-MeO-DMT gives rise to a global coherent state (the so-called “unified energy field”), whereas DMT gives rise to an ecosystem of time-loops, each trying to capture as much of your attention as possible, which in turn results in coalition-building and evolution of patterns in the direction of being very “attention grabbing” (cf. reddit.com/r/place).
B) Really Positive or Really Negative Valence vs. Highly-Mixed Valence: 5-MeO-DMT gives rise to either a globally coherent state (high-valence) or two competing coherent states (negative-valence), whereas DMT tends to generate complex consonance/dissonance relationships between the clusters of coherence.
C) How they are different according the the Free Energy Principle: On 5-MeO-DMT the entire experience has to reinforce itself, whereas each cluster of coherence needs to model the rest of the experience in order to be reinforced by it on DMT. Thus 5-MeO-DMT makes experiences that express “the whole as the whole” whereas DMT makes each part of the experience represent the whole yet remains distinct.
And the original 9 lenses:
1) Space vs. Form: 5-MeO is more space-like than DMT. 2) Crystals vs. Quasi-Crystals: 5-MeO generates more perfectly repeating rhythms and hallucinations than DMT. 3) Non-Attachment vs. Attachment: 5-MeO seems to enable detachment from the craving of both existence and non-existence, whereas DMT enhances the craving. 4) Underfitting vs. Overfitting: 5-MeO reduces one’s model complexity whereas DMT radically increases it. 5) Fixed Points and Limit Cycles vs. Chaotic Attractors: 5-MeO’s effect on feedback leads to stable and predictable attractors while DMT’s attractors are inherently chaotic. 6) Modulation of Lateral Inhibition: 5-MeO may reduce lateral inhibition while DMT may enhance it. 7) Diffuse Attention vs. Focused Attention: 5-MeO diffuses attention uniformly over large regions of one’s experiential field, while DMT seems to focus it. 8) Big Chunks and Tiny Chunks vs. A Power Law of Chunks: 5-MeO creates a few huge phases of experience (as in phases of matter) with a few remaining specks, while DMT produces a more organic power law distribution of chunk sizes. 9) Integration vs. Fragmentation: 5-MeO seems to give rise to “neural integration” involving the entrainment of any two arbitrary subnetworks (even when they usually do not talk to each other), while DMT fragments communication between most networks but massively enhances it between some specific kinds of networks.
I also explain what is going on with the “Megaminx DMT worlds” and when DMT entities bully you into believing in their independent existence.
Digital Sentience: Can Digital Computers Ever “Wake Up”? (link)
I start by acknowledging that most smart and well-informed people today believe that digital computers can be conscious. More so, they believe this for good reasons.
In general, 99.99% of the times when someone says that digital computers cannot be conscious they do so equipped with very bad arguments. This, of course, does not mean that all of these smart people who believe in digital sentience are right. In fact, I argue that they are making a critical yet entirely non-obvious mistake: they are not taking into account a sufficiently detailed set of constraints that any scientific theory of consciousness must satisfy. In this video I go over what those constraints are, and in what way they actually entail that digital sentience is literally impossible.
The talk is divided into three parts: (1) my philosophical journey, which I share in order to establish credibility, (2) classic issues in philosophy of mind, and (3) how we can solve all those issues with QRI’s theory of consciousness.
(Skip to 31:00 if you are not interested in my philosophical journey and you want to jump into the philosophy of mind right away).
(1) I’ve been hyper-philosophical all my life and have dedicated thousands of hours working on this topic: having discussions with people in the field, writings essays, studying qualia in all manners of exotic states of consciousness, and working through the implications of different philosophical background assumptions. I claim that QRI’s views here are indeed much more informed than anyone would assume if they just heard that we think digital computers cannot be conscious. In fact, most of us started out as hard-core computationalists and only switched sides once we fully grokked the limitations of that view! Until the age of 20 I was a huge proponent of digital sentience, and I planned my life around that very issue. So it was a big blow to find out that I was neglecting key pieces of the puzzle that David Pearce, and later Mike Johnson, brought up when I met them in person. In particular, they made me aware of the importance of the “phenomenal binding/boundary problem”; once I finally understood it, everything unraveled from there.
(2) We go over: Marr’s levels of analysis (and “interactions between levels”). The difference between functionalism, computationalism, causal structure, and physicalist theories of consciousness. The Chinese Room. Multiple Realizability. Epiphenomenalism. Why synchrony is not enough for binding. Multiple Drafts Theory of consciousness. And the difference between awareness and attention.
(3) We solve the boundary problem with topological segmentation: this allows us to also provide an explanation for what the causal properties of experience are. The integrated nature of fields can be recruited for computation. Topological boundaries are neither epiphenomenal nor frame-dependent. Thus, evolution stumbling upon holistic field behavior of topological pockets of the fields of physics would solve a lot of puzzles in philosophy of mind. In turn, since digital computers don’t use fields of physics for computation, they will never be unified subjects of experience no matter how you program them.
I also discuss issues with IIT’s solution to the binding problem (despite IIT’s whole aesthetic of irreducible causality, their solution makes binding epiphenomenal! The devil’s in the details: IIT says the Minimum Information Partition has “the highest claim of existence” but this leaves all non-minimal partitions untouched. It’s epiphenomenal and thus not actually useful for computation).
Thanks also to Andrew Zuckerman and other QRI folks for great recent discussions on this topic.
Psychedelics and the Free Energy Principle: From REBUS to Indra’s Net (link)
Friston’s Free Energy Principle (FEP) is one of those ideas that seem to offer new perspectives on almost anything you point it at.
It seems to synthesize already very high-level ideas into an incredibly general and flexible conceptual framework. It brings together thermodynamics, probabilistic graphical models, information theory, evolution, and psychology. We could say that trying to apply the FEP to literally everything is not a bad idea: it may not explain it all, but we are bound to learn a lot from seeing when it fails.
So what is the FEP? In the words of Friston: “In short, the long-term (distal) imperative — of maintaining states within physiological bounds — translates into a short-term (proximal) avoidance of surprise. Surprise here relates not just to the current state, which cannot be changed, but also to movement from one state to another, which can change. This motion can be complicated and itinerant (wandering) provided that it revisits a small set of states, called a global random attractor, that are compatible with survival (for example, driving a car within a small margin of error). It is this motion that the free-energy principle optimizes.“
Organisms that survive over time must minimize entropy injections from their environment, which means they need to minimize surprise, which unfortunately is computationally intractable, but the information theoretic construct of variational free-energy provides an upper bound on this ground truth surprise, meaning that minimizing it will indirectly minimize surprise. This cashes out in the need to maximize “accuracy – complexity” which prevents both overfitting and underfitting. In the video we go over some of the classical ideas surrounding the FEP: the dark room, active inference, explicit vs. implicit representations, and whether real dynamic systems can be decomposed into Markov blankets. Finally, we cover how the FEP naturally gives rise to predictive coding via hierarchical Bayesian models.
We then talk about Reduced BEliefs Under pSychedelics (REBUS) and explain how Carhart-Harris and Friston interpret psychedelics and the Anarchic Brain in light of the FEP. We then discuss Safron’s countermodel of Strengthened BEliefs Under pSychedelics (SEBUS) and the work coming out of Seth’s lab.
So, that’s how the FEP shows up in the literature today. But what about explaining not only belief changes and perceptual effects, but perhaps also getting into the actual weeds of the ultra bizarre things that happen on psychedelics?
I provide three novel ideas for how the FEP can explain features of exotic experiences:
(1) Dissonance-minimizing resonance networks would naturally balance model complexity due to an inherent “complexity cost” that shows up as dissonance and prediction error minimization when prediction errors give rise to out-of-phase interactions between the layers.
(2) Bayesian Energy Sinks: What you can recognize lowers the (physical) energy of one’s world-sheet. I then blend this with an analysis of symmetrical psychedelic thought-forms as energy-minimizing configurations. On net, we thus experience hybrid “semantic + symmetric” hallucinations.
(3) Indra’s Net: Each “competing cluster of coherence” needs to model its environment in order to synch up with it in a reinforcing way. This leads to attractor states where “everything reflects everything else”.
Advanced Visions of Paradise: From Basic Hedonism to Paradise Engineering (link)
This video was recorded as a way for me to prepare for the speech I gave at the “QRI Summer Party 2021: Advanced Visions of Paradise” (see livestream here). You can think of it as the significantly more in-depth (and higher audio quality!) version of that speech.
The core message of this video is: thinking wholesome, genuinely useful, and novel thoughts about how to build paradise is hard. Doing so without getting caught up in low-dimensional aesthetics and pre-conceptions is very challenging. Most of the “visions of paradise” we find in our culture, media, and art are projections of implicit aesthetics used for human coordination, rather than deeply thought-out and high-dimensional perspectives truly meant to elevate our understanding and inspire us to investigate the Mystery of reality. Aesthetics tend to put the cart before the horse: they tacitly come with a sense of what is good and what is real. Aesthetics are fast, parallel, and collective ways of judging the goodness or badness of images, ideas, and archetypes. They give rise to internal dissonance when you present to them things that don’t fit well with their previous judgements. And due to naïve realism about perception, these judgements are often experienced as “divine revelations”.
To disentangle ourselves from tacit low-dimensional aesthetics, and inspired by the work of Rob Burbea (cf. Soulmaking), I go over what aesthetics consist of: Eros, Psyche, and Logos. Then, to explore high-quality aesthetics relevant to paradise engineering, I go over 7 camps of a hypothetical “Superhappiness Festival”, each representing a different advanced aesthetic: Hedonism, Psychiatry, Wholesome, Paleo, Energy, Self-Organization, and Paradise Engineering. For didactic purposes I also assign a Buddhist Realm (cf. “Opening the Heart of Compassion” by Short & Lowenthal) to each of the camps.
Note: the Buddhist realms are a very general lens, so a more detailed exposition would point out how each of the camps manifests in each of the Buddhist realms. Don’t put too much stock on the precise mapping I present in this video.
~Qualia of the Day: Pure Lands~
Picture by Wendi Yan (wendiyan.com) “The Tower of Paradise Engineering” (also the featured image of this post / image to appear in the forthcoming QRI Book)
For context, here is the party invite/description:
Science fiction and futurism have failed us. Simply put, there is a remarkable lack of exploration when it comes to the role that consciousness (and its exotic states) will play in the unfolding of intelligent agency on Earth. This, of course, is largely understandable: we simply lack adequate conceptual frameworks to make sense of the state-space of consciousness and its myriad properties. Alas, any vision of the future that neglects what we already know about the state-space of consciousness and its potential is, in the final analysis, “missing the point” entirely.
Exotic states of consciousness are consequential for two reasons: (1) they may provide unique computational benefits, and (2) they may have orders of magnitude more bliss, love, and feelings of inherent value. As Nick Bostrom puts it in Letter From Utopia:
(1) “Mind is a means: for without insight you will get bogged down or lose your way, and your journey will fail.
(2) “Mind is also an end: for it is in the spacetime of awareness that Utopia will exist. May the measure of your mind be vast and expanding.”
In light of the above, let us for once try to be serious consciousness-aware futurists. Then, we must ask, what does paradise look like? What does it feel like? What kinds of exotic synesthetic thought-forms and hyper-dimensional gems populate and imbue the spacetime of awareness that makes up paradise?
Come and join us for an evening of qualia delights and great company: experience and make curious smells, try multi-sensory art installations, and listen to a presentation about what we call “Advanced Visions of Paradise”. Equipped with an enriched experience base and a novel conceptual toolkit, we look forward to have you share your own visions of paradise and discuss ways to bring them into reality.
Ps. If you are being invited to this event, that means that we value you as a friend of QRI ❤
Pss. Only come if you are fully vaccinated, please!
~Music: People were asking me about the playlist of yesterday’s party. The core idea behind this playlist was to emulate the sequence of aesthetics I talked about in the speech. Namely, the songs are ordered roughly so that each of the 7 camps gets about 1 hour, starting in camp Hedonism and going all the way to camp Paradise Engineering: QRI Summer Party 2021: Advanced Visions of Paradise~
Excerpt from The Science of Enlightenment (2005) by Shinzen Young (p. xv-xvii)
It took me quite a while to get to the point of publishing this book — many years actually. That may seem like a strange statement. How can someone not get the point of publishing something they themselves wrote? Let me explain.
A central notion of Buddhism is that there’s not a thing inside us called a self. One way to express that is to say that we are a colony of sub-personalities and each of those sub-personalities is in fact not a noun but a verb–a doing.
One of my doings is Shinzen the researcher. Shinzen the researcher is on a mission to “take the mist out of mysticism.” Contrary to what is often claimed, he believes that mystical experience can be described with the same rigor, precision, and quantified language that one would find in a successful scientific theory. In his opinion, formulating a clear description of mystical experience is a required prenuptial for the Marriage of the Millennium: the union of quantified science and contemplative spirituality. He hopes that eventually this odd couple will exuberantly make love, spawning a generation of offspring that precipitously improves the human condition.
Shinzen the researcher also believes that many meditation masters, current and past, have formulated their teachings with “less than full rigor” by making unwarranted, sweeping philosophical claims about the nature of objective reality based on their subjective experiences—claims that tend to offend scientists and, hence, impede the science-spiritually courtship.
Shinzen the researcher has a natural voice. It’s the style you would find in a graduate text on mathematics: definition, lemma, theorem, example, corollary, postulate, theorem. Here’s a sample of that voice:
It may be possible to model certain global patterns of brain physiology in ways that feel familiar to any trained scientist, i.e., equations in differential operators on scalar, vector, or tensor fields whose dependent variables can be quantified in terms of SI units and whose independent variables are time and space (where space equals ordinary space or some more esoteric differential manifold). It is perhaps even possible to derive those equations from first principles the way Navier-Stokes is derived from Cauchy continuity. In such fields, distinctive “flow regimes” are typically associated with relations on the parameters of the equations, i.e., F(Pj) → Q, where Q is qualitative change in field behavior. By qualitative change in field behavior, I mean things like the appearance of solitons or the disappearance of turbulence, etc. Through inverse methods, it may be possible to establish a correspondence between the presence of a certain parameter relation in the equations modeling a field in a brain and the presence of classical enlightenment in the owner of that brain. This would provide a way to physically quantify and mathematically describe (or perhaps even explain) various dimensions of spiritual enlightenment in a way that any trained scientist would feel comfortable with.
That’s not the voice you’ll be hearing in this book. This book is a record of a different Shinzen, Shinzen the dharma teacher, as he talks to students engaged in meditation practice. Shinzen the dharma teacher has no resistance at all to speaking with less than full rigor. He’s quite comfortable with words like God, Source, Spirit, or phrases like “the nature of nature.” In fact, his natural voice loves spouting the kind of stuff that makes scientists wince. Here’s an example of that voice:
The same cosmic forces that mold galaxies, stars, and atoms also mold each moment of self and world. The inner self and the outer scene are born in the cleft between expansion and contraction. By giving yourself to those forces, you become those forces, and through that, you experience a kind of immortality–you live in the breath and pulse of every animal, in the polarization of electrons and protons, in the interplay of the thermal expansion and self-gravity that molds stars, in the interplay of dark matter that holds galaxies together and dark energy that stretches space apart. Don’t be afraid to let expansion and contraction tear you apart, scattering you in many directions while ripping away the solid ground beneath you. Behind that seeming disorder is an ordering principle so primordial that it can never be disordered: father-God effortlessly expands while mother-God effortlessly contracts. The ultimate act of faith is to give yourself back to those forces, give yourself back to the Source of the world, and through that, become the kind of person who can optimally contribute to the Mending of the world.
Shinzen the hard-nosed researcher and Shinzen the poetic dharma teacher get along just fine. After all, they’re both just waves. Particles may bang together. Waves automatically integrate. Just one problem though. The researcher is a fussy perfectionist. He is very resistant to the notion of publishing anything that lacks full rigor. Spoken words return to silence from where they came from. Printed text sits around for centuries waiting for every tiny imprecision and incompleteness to be exposed.
So it took a while for me to see value in allowing my talks to be published in something close to their original spoken form.
This video discusses the connections between meditative flow (any feeling of change) and the two QRI paradigms of “Wireheading Done Right” and “Neural Annealing“. To do so, I explore how each of the “seven factors of awakening” can be interpreted as operations that you do to flow. In a nutshell: the factors are “energy management techniques”, which when used in the right sequences and dosages, tend to result in wholesome neural annealing.
I then go on to discuss two fascinating dualities: (1) The dual relationship between standing wave patterns and vibratory frequencies. And (2) the dual correspondence between annealing at the computational level (REBUS) and annealing in resonance networks.
(1) Describes how the crazy patterns that come out of meditation and psychedelics are not irrelevant. They are, in a way, the dual counterpart to the emotional processing that you are undergoing. Hence why ugly emotions manifest as discordant structures whereas blissful feelings come together with beautiful geometries.
(2) Articulates how simulated annealing methods in probabilistic graphical models such as those that underlie the synthesis of entropic disintegration and the free energy principle (Friston’s and Carhart-Harris’ REBUS model) describe belief updating. In contrast, annealing at the implementation level refers to a dissonance-minimization technique in resonance networks. In turn, if these are “two sides of the same coin”, we can expect to find that operations in one domain will translate to operations in the other domain. In particular, I discuss how resisting information (“denial”, “cognitive dissonance”) has a corresponding subjective texture associated with muscle tension, “resistance”, viscosity, and hardness. Equanimity, in turn, allows the propagation of both waves of dissonance, consonance, and noiseas well as bundles of information. This has major implications for how to maximize the therapeutic benefit of psychedelics.
Finally, I explain how we could start formalizing Shinzen Young’s observation that you can, not only “read the contents of your subconscious“, but indeed also “heal your subconscious by greeting it with enough concentration, clarity, and equanimity”. Negentropy in the resonance network (patches of highly-ordered “combed” coherent resonance across levels of the hierarchy) can be used to heal patches of dissonance. This is why clean high-valence meditative objects (e.g. metta) can absorb and dissipate the internal dissonance stored in patterns of habitual responses. In turn, this might ultimately allow us to explain why, speaking poetically, it is true that love can heal all wounds. 🙂
~Qualia of the Day: Nirvana Rose~
(Skip to ~10:00 if you don’t need a recap of Wireheading Done Right and Neural Annealing)
Imagine that you were tasked with creating a molecule to represent the spirit of California. I think that I would just glue together two MDMA molecules and call it a day.
It turns out Californidine is indeed a real molecule, named after the California Poppy. I am still wrapping my head around the fact that Californidine can be described as two MDMA molecules sharing the nitrogen atom and with the end of the carbon chain of each MDMA molecule bonded at the 2-position of the benzene ring of the other one (minus a hydrogen atom). Interestingly, this compound has no psychedelic or empathogenic action. At best, it can be described as a very mild and unreliable relaxing agent of “herbal strength” akin to the active ingredients of chamomile, valerian, or ashwagandha. So, joining two powerful heart-openers gives rise to a mild sleep-inducer? Perhaps this is a metaphor for something.
Californidine and MDMA
But that’s not what I want to talk to you about today. While gluing together psychoactive molecules may not have a (cartoonishly) desirable additive effect, doing so does express the spirit of what I want to propose today. And that is the impulse to use a creative and fun approach to drug design, letting your imagination run wild to avoid prematurely discarding one’s crazy ideas.
Notable Leads for Great Drug Combos
Over the last 10 years I’ve read many (many!) trip reports and have talked to hundreds of experienced psychonauts (see also: r/replications). It is largely thanks to a subset of these psychonauts, which for lack of a better term could be described as the subset of rational psychonauts, that I’ve been able to assemble empirically testable models for psychedelic phenomenology (some examples: Algorithmic Reduction of Psychedelic States, Hyperbolic Geometry of DMT Experiences, Quantifying Bliss, How to Secretly Communicate with People on LSD, etc.). Although my focus has largely been on the effects of individual drugs, I’ve become very cognizant of the fact that drug combinations can produce effects not accessible with individual substances. In other words, when it comes to mixing psychoactive substances, the sum is more often than not different from the sum of its parts. Some of these effects seem extremely significant both from a scientific and a philosophical point of view.
But first, an important disclaimer: mixing drugs is dangerous and you should never do it unless you really know what you are doing. The pile of celebrity deaths caused by multiple drug intoxication is only scratching the surface. Indeed, there are many combinations of drugs that are deadly even when the individual drugs taken on their own are relatively safe. For example, while 5-MeO-DMT is relatively safe when vaporized (save for egregiously negligent uses of the drug and the occasional drowning in one’s own vomit), taking 5-MeO-DMT orally in combination with an MAOI leads to extremely toxic reactions, such as severe hypertensive symptoms, overheating, and serotonin syndrome. Don’t do it. As a very rough guide for how mixtures of psychoactives behave, study the chart below.
Welcome to the practice of combining drugs. You may die. (source)
That said, just as drug combinations have a dangerous side, they also likely harbor hidden gems that are very safe, enjoyable, and mind-expanding in ways inaccessible via single drugs. As a general overview, some examples of the possible benefits of drug combinations include: (1) Enhanced euphoria, e.g. see speedball which is massively euphoric but also very dangerous, (2) reduced psychological discomfort (e.g. anxiolytics with psychedelics), (3) uniquely interesting effects, e.g. LSD + MDMA (see below), and (4) reduced physical side-effects and medical risks, e.g. calcium blockers to reduce MDMA neurotoxicity, 5HT2B antagonists to reduce cardiotoxicity of psychedelics, etc. as we’ll discuss. In addition, it is worth mentioning that from a therapeutic point of view, we also have the “more dakka effect“, where some conditions only respond to combining enough drugs (e.g. oncology). It’s possible chronic pain or severe depression may legitimately require multiple drugs to be adequately dealt with. Now let us examine in more detail some particularly interesting categories of drug combinations:
Psychedelics + Anxiolytics: According to many reports, phenibut in small doses seems to significantly reduce the anxiety that comes up on psychedelics. I am ambivalent about sharing this information given the fact that phenibut can become a huge problem for some people, but I think that on the whole it is wise for people to know that an over-the-counter “nootropic” can actually help avoid fear, discomfort, and panic attacks during a psychedelic experience.
Cannabis + Psychedelics: I generally find two kinds of psychedelic drug users. Those who cannot think of having a psychedelic trip without at some point smoking a joint, vaping, or eating a cannabis edible. And then those who would never dare to combine the two because they once had a terrifying experience with the combo. Interestingly, some of the people I’ve met over the years who seem to be able to easily handle massive doses of psychedelics (e.g. 500 micrograms of acid) respond terribly to weed, and especially badly if they are already tripping. Cannabis both modifies and potentiates psychedelic states of mind. It has a tendency to make the experience more conceptual rather than sensory or mystical. The combination also greatly increases the probability of getting stuck in time loops.
Empathogens + Psychedelics: One of the best descriptions of MDMA + LSD (also called candy-flipping) that I’ve found comes from Steven Lehar (emphasis added):
Under LSD and ecstasy I could see the flickering blur of visual generation most clearly. And I saw peculiar ornamental artifacts on all perceived objects, like a Fourier representation with the higher harmonics chopped off. LSD by itself creates sharply detailed ornamental 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.
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.
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.
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**:
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:
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):
2C-T-2: Error of 1.31
DOB: Error of 1.51
Aleph-2: Error of 1.85
2C-B: Error of 2.34
2C-B-fly: Error of 2.76
Ibogaine: Error of 7.05
MDMA: Error of 7.06
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.
Iso E Super
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:
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.
[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).
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
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 withanti-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.
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“.
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.
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!
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.
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 intelligence; BGI). 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.”
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.)
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.
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.
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).
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).
Tianeptine (its effects on the delta opioid receptor attenuates its tolerance when used in therapeutic doses)
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)