The Psychedelic Renaissance — Part 2
Brain chemistry and brain networks — using psychedelics to rewire the brain.
My previous blog post covered the history and the potential impact of the Psychedelic Renaissance. Now, we’ll dive into the science a bit more and uncover why these compounds have the impact that has been described. It’s worth taking a moment to understand a revolution that is happening within the field of neuroscience as well. For a long time neuroscience was really split between two scales. On the one hand, were the molecular neurobiologists — really digging in and understanding the composition and chemistry of the synapse, which is the major communication unit of neurons in the brain. They went to work cataloging each protein, receptor and neurotransmitter that entered the synapse and did its work exciting, inhibiting or modulating the firing of neurons. This was amazing work, no question. At the other scale, were the cognitive neuroscientists who were less concerned with the firing of individual neurons and more interested in the areas of the brain that “light up” during specific tasks and thought processes. They used tools like PET scans and fMRI to see specifically which regions of the brain were activated or deactivated during tasks. I have, at times in a humorous tone, called this “blob-ology” — because it really was focused on regional activation rather than the brain in concert, as a whole. More recently, neuroscientists have been taking a more holistic view of the brain’s activity, spurred in part by research on the connectome. This builds upon the idea that while individual regions of the brain are certainly associated with aspects or behaviors, it is really the brain as a highly interconnected network that really drives our experience. It is here where we link back up with the story of psychedelic medicines. Originally, when subjects were placed in cognitive task environments and had their brains scanned, researchers assumed that when not otherwise tasked — the brain was resting — or not engaged in meaningful activity. This was proven wrong when in the 2000’s it was shown that the brain was actually quite active in this supposed “resting” state. In 2001, Dr. Marcus Raichle, coined the term “default mode network” (DMN) — which through further research has been shown to be active during thoughts about autobiographical information, emotion’s about oneself and self-reference, among other things. Not so quiet after all! In talks I often refer to this jokingly as the “thinking about thinking about oneself” network. It is the quintessential monkey-mind network. The work of Dr. Judson Brewer at Brown University, showed that it was precisely activity in this network that decreased in the brains of experienced meditators. The DMN is a complex network with subsystems, each of which may play a unique role. While the neural system is complex, the pieces have started to fit together. Further studies involving brain imaging in studying depression and trauma seemed to indicate that these mental health conditions may in part, be dysfunctions of the systems in the default mode network. It’s ruminative nature may run amok and shift the brain toward depressive states that it can not break out of. And not surprisingly, both psilocybin and LSD have effects on the DMN functioning in the brain. In a first-of-its-kind study, Dr. Robin Carhart-Harris showed through brain imaging the effect of psilocybin on the brain. It reduces the activity in the DMN. Ok, now this is getting exciting.
The clinicians and researchers who began working with psychedelic compounds in the 1950’s and 1960’s didn’t have the tools to understand what was happening in the brain during these experiences. The DMN wouldn’t even be discovered until the next century! They just knew it worked, but they couldn’t explain why. Now, during the psychedelic renaissance we have the tools to put ALL of the pieces together. For a current review, see Dr. Carhart-Harris’ excellent review of the landscape.
Patients who are treated with psychedelics, especially those who have meaningful doses in controlled therapeutic experiences, often report something akin to “ego death” — their sense of self dissolving away, and this element is recorded as a significant clinical event. Now that we understand the role of the DMN in reinforcing our sense of self, it makes sense why these compounds are able to undo that. Certainly the DMN is not the ONLY answer here, but it’s role seems very important both neurophysiologically and therapeutically. While I won’t delve deeply here into the variations in serotonergic receptor sub-types, it is important to note that molecular neurobiology and network based cognitive neuroscience are now working in concert to understand both the synaptic mechanism of action of these drugs and simultaneously understand their network effects in the brain.
We are fortunate that we don’t have just one compound to explore, we have many. We have the tryptamines, known as serotonergic hallucinogens: LSD, psilocybin and 5MeO-DMT, ayahuasca (DMT) and ibogaine are in this category. MDMA, a methamphetamine compound, also targets the serotonergic system through transporter reversal, thus causing the release of serotonin at synapses. Ketamine, historically an anesthetic, is an NMDA receptor antagonist, and the newer enantiomer, esketamine has recently been approved as a nasal spray for treatment-resistant depression. Note again, ketamine is the only currently approved treatment that is available outside of a clinical trial (e.g. by prescription in a clinic) in the US. The compounds, while at times causing similar effects, can demonstrate different mechanisms of action and may be useful in different therapeutic conditions. After the tireless efforts of researchers, MDMA received breakthrough therapy designation by the FDA in 2017 for PTSD and psilocybin received the same designation for major depressive disorder starting in 2018. While these designations won’t change the current scheduling status of the drugs, it opens up the pathway for their eventual approval and use in the clinic. Currently all of the compounds listed above are in clinical trials for addiction, anorexia, anxiety, migraines, depression, PTSD and OCD.
In addition to the core compounds themselves, a renaissance in medicinal chemistry now flourishes to help find either novel agonists, enantiomers, or even entirely NEW chemical entities that have similar medicinal properties with a wider range of potential applications. For example, while an 8 hour psilocybin trip may be transformative, it may not be for everyone! It is important to explore shorter acting compounds. Clinical studies currently involving microdoses of the current tryptamines are studying if the entire psychedelic “trip” is necessary to reap the benefits of the resetting might occur. Can a psychedelic become ‘merely’ psychoactive and have the same effect? This is particularly important because patients who have been on long-term therapies for treatment-resistant depression may need to consider other pharmacological targets, as long-term use of antidepressants make them poor candidates for the mechanism of action utilized by psilocybin. Additionally, with the staggering numbers of individuals facing the mental health conditions above, there will need to be a revolution in treatment delivery that accompanies the renaissance. Hundreds of millions of individuals would be candidates for this life-changing treatment. Some clinicians are currently contemplating a “deep experience + maintenance” combination. This means a patient would have a longer transformative experience to “reset” the brain and then a lower dose continued treatment to ensure the brain pathways are completely rewired.
Currently, an ‘in clinic’ approach is advocated for the delivery of these medicines. While the treatment space is evolving, those like Field Trip Health and others are focusing on ketamine treatments for now — while paving the way for the integration of other current compounds whose status may transition from illegal to prescription. The clinicians in the field are quick to remind that the “set and setting” and integration post therapy are as important as the medicines themselves in realizing the transformative results. Outside of the US, retreat centers are offering similar experiences for those willing, as individuals have been for decades, to travel for access to these medicines.
I would be remiss if I didn’t mention the excitement around the new companies appearing on the scene to address multiple aspects of this psychedelic renaissance. In particular the number of companies developing new compounds is exploding. Some companies like atai life sciences are focusing on a combined approach, building a portfolio of companies to address various clinical targets. Others like CaaM Tech, Gilgamesh Pharmaceuticals and Beckley Psytech (among many) are targeting new compounds to help increase the toolkit of available compounds for clinical use. It’s worth tracking all of these companies on the excellent source psilocybin alpha which is one of the best ways to stay up to date. I expect we will see more listings and even a few IPOs that will absolutely be worth watching in 2021.
But to anchor it all back in reality, the most important thing is that these transformative medicines make it into the lives of the people who need them most. That is truly science in the service of mankind. We hope that you will join us on this journey, and attend our Webinar on February 17, 2021. Please register at this link. We are excited about exploring the possibilities with you.
Prime Movers Lab invests in breakthrough scientific startups founded by Prime Movers, the inventors who transform billions of lives. We invest in companies reinventing energy, transportation, infrastructure, manufacturing, human augmentation, and agriculture.
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