In the paper Psychedelics and the Human Receptorome by Thomas Ray there is a supplementary material table that is one of my favorite datasets of all time. I keep a copy of it on my laptop, with some extra color-coding, and every now and then open it and just think about what this table is trying to tell us. The rows are drugs and the columns are receptor proteins expressed on neurons; the values are binding affinities, a measure of how strongly the drug interacts with the receptor.
Through the lens of the spike, we can think of the brain as a dynamical system whose state corresponds to the collective (“population”) firing activity. But we have to remember that the actual communication between neurons is mostly chemical, not electrical. If the only thing that mattered was spikes, evolution probably wouldn’t have developed the hundreds of neurotransmitters that actually transduce the signals across each synapse. 1
One reason evolution may have done this is if it simplified the inherent optimization problem by making it possible to tune separate neural “sub-systems” somewhat independently rather than having the whole thing so tightly coupled all the way through. This interpretation gives us a sense in which these receptors are essentially principal components of some abstract cognitive phase space. Understanding the geometry of this space is a central aim of neuroscience, since it would tell us a lot about how our brains work and why they look the way they do.
Psychedelics are pharmacological agents that act on these receptors and deform neural activity, leading to their signature hallucinogenic effects. As it turns out, many psychedelics are actually very safe in humans. (Physiologically: they are not toys and are for sure capable of causing psychological damage when mis-used.) This creates a promise of precision interrogation of neural processing along the dimensions of these receptor systems, potentially allowing us to dissect cognition and study it far more deeply than we have previously without an implant.
Dr. Ray’s research is arguably the continuation of the scientific program Alexander Shulgin began in the 1960s. While it may sound hard to believe today, all of Dr. Shulgin’s data was collected legally, as of course were the datasets in Dr. Ray’s papers. With the era of prohibition seemingly winding down on the heels of the successes of MDMA-assisted psychotherapy for PTSD, and ketamine and psilocybin for depression, to say nothing of growing cannabis legalization or the hundreds of millions of dollars raised by dozens of psychedelic commercialization startups, it feels like a window is opening to do serious, potentially breakthrough research and translate it into important therapies. As I write often here, in a very deep sense you are your brain, and better drugs have an important and complementary role to play alongside better optical and electrophysiological methods in engineering the brain.
Thomas Ray has teamed up with Dillan DiNardo, an entrepreneur who most recently did biopharma and medical device investing for UPMC, a major healthcare system in Pittsburgh, to start Mindstate Design Labs. Their goal is to pursue Dr. Ray’s “mental organs” hypothesis and hopefully gain a more detailed understanding of how and why psychedelics work with the aim of engineering better ones. I’m delighted to back Thomas and Dillan as part of an $11.5M round led by Initialized. It’s super early for Mindstate’s work, but I’m excited to see where the science takes us!
1. Indeed, there are only a couple pure “fast” neurotransmitters, mainly glutamate which is excitatory and GABA which is inhibitory, and these represent the vast majority of synapses in the human brain. In effect evolution has discovered a 2-bit “basic” spike, where glutamate signals a “positive” input to the post-synaptic neuron and GABA signals a “negative” input. While other neurotransmitters can also cause “fast” ion flows, the interesting effects associated with things like serotonin, dopamine or opioid receptors are metabolic effects in the downstream neuron. This kind of “slow synaptic transmission” is enormously more complicated than most people ever think about and won a Nobel Prize in 2000.