Video Summary
Classical psychedelics (LSD, DMT, psilocybin) make neurons fire asynchronously, injecting 'noise' that reconstructs perception.
Bryan L. Roth solved receptor structures and is developing non‑hallucinogenic compounds that target the same receptors as psychedelics.
Ibogaine and salvinorin A act on the kappa opioid receptor and produce distinct, often brutal, oneirogenic or psychotomimetic experiences.
The claustrum contains both 5‑HT2A and kappa receptors and may be a hub where different reality‑altering systems converge.
Roth's lab uses AI and ultra‑large docking to screen virtual libraries of up to a trillion compounds to design novel drugs in silico.
He aims to design compounds that engage therapeutic signaling at psychedelic targets (like 5‑HT2A) without producing the subjective hallucinogenic trip—using biased agonism and structure‑guided design, supported by DARPA funding.
They cause layer‑5 pyramidal neurons and related circuits to fire asynchronously, effectively injecting noise into perception networks so the brain reconstructs reality in novel, often highly meaningful ways.
Kappa agonists (e.g., salvinorin A, components of ibogaine effects) produce psychotomimetic experiences and are co‑located with 5‑HT2A receptors in the claustrum, a proposed hub for perception—suggesting multiple receptor systems can alter reality construction.
AI enables ultra‑large virtual screening of up to a trillion never‑synthesized molecules to design candidate drugs in silico, dramatically expanding chemical space and accelerating hit discovery—though choosing the right biological target remains the bigger challenge.
"What happens with classical psychedelics is these neurons start firing in this very asynchronous fashion."
"Brian Roth is one of the world's leading pharmacologists and a pioneer in psychedelic research."
"Ibogaine is still a mysterious substance. It can be a very rough experience."
"The kappa receptor is found in many of the same brain regions as the 5-HT2A receptor, particularly in the claustrum."
"My mother was diagnosed with schizophrenia around the time I was five or six."
"For many patients, it can be a transformative experience."
The discussion highlights the impact of psychedelics such as psilocybin, DMT, and LSD on individuals suffering from depression or PTSD. Many patients find these substances to be life-changing, although they may not work for everyone.
The speaker mentions a personal story of a close friend who underwent a significant transformation after receiving psychedelic therapy in Australia. This friend appeared brighter and more alive, illustrating the potential benefits of psychedelics in treating mental health issues.
"I've witnessed friends pull themselves out of despair through self-experimentation."
The speaker provides additional examples from their circle where friends managed to escape from deep despair through self-experimentation with LSD. One friend transitioned from being unable to get out of bed to becoming gainfully employed and graduating from college—an unimaginable turnaround in his life over a decade.
Another compelling story comes from a Vietnam veteran who shared his journey with ibogaine and psilocybin, indicating they helped him recover from severe PTSD. He felt as though he was at the brink of life or death but emerged "completely fine" after these experiences.
"Ibogaine is still a mysterious substance."
Ibogaine, derived from the root of a plant in Africa, has been used traditionally for healing. It has garnered attention in recent years, especially after a new executive order aimed at facilitating research into psychedelics.
Although ibogaine is not classified as a classic psychedelic, it is known for its hallucinogenic properties. It is categorized as an oneirogen, inducing a dream-like state, often linked to its kappa opioid receptor agonism.
The mechanism of ibogaine's transformative effects remains unclear and is a subject of investigation. The speaker's lab has yet to uncover other potential brain targets that may be involved, highlighting the ongoing mysteries surrounding its impact on recovery.
"It's a pretty rough experience, pretty brutal."
Ibogaine experiences can be challenging and last for 12 to 24 hours, where individuals might confront painful memories or guilt from their past. Some report feeling as if they were reliving times when they caused pain to others, leading to a profound transformation.
Despite its potential benefits, there are significant risks associated with ibogaine use, including the possibility of fatal arrhythmias, especially when combined with certain over-the-counter medications. This necessitates monitoring and caution when administering ibogaine in clinical settings.
Clinics are now adopting safety measures, including EEG and EKG monitoring, and administering magnesium to reduce the risk of cardiac issues, reinforcing the seriousness of this medication and the need for professional guidance.
"Kappa agonists are psychotomimetic."
The kappa opioid receptor, discovered in the 1970s, is known for its unique effects that are not mirrored by classical opioid agonists. Research has identified bremazocine as a potent kappa agonist that induces hallucinatory experiences in humans, although these findings have often been overlooked in the opioid research community.
Despite early studies indicating kappa agonists could induce hallucinations, they were largely dismissed because these agonists were associated with dysphoria rather than euphoria. As a result, the perception of kappa agonists being ineffective for pain relief arose since inducing a psychotic experience is contraindicated for analgesic properties.
The compound salvinorin A, identified as a selective kappa agonist, has confirmed the psychotomimetic effects associated with kappa receptor activity. Notably, salvinorin A targets this receptor with very high affinity and has generated interest for its hallucinogenic properties.
"The claustrum has long been thought to be a hub for perception."
Research indicates that both kappa opioid receptors and 5-HT2A serotonin receptors are located in the claustrum, a brain region that may play a crucial role in constructing perceptions of reality. The claustrum has garnered attention from researchers, including those studying consciousness, for its potential influence in how we experience our surroundings.
There is a hypothesis suggesting that different psychedelics, such as LSD and psilocybin (which target 5-HT2A receptors) and salvia or ibogaine (which act on kappa receptors), might engage similar neural pathways, although the subjective experiences differ.
"The experience is different, right?"
While the mechanisms of various psychedelic substances may invoke changes in reality perception, the subjective experiences are distinct. Experiences with psychedelics like LSD are described as fundamentally different from those induced by ibogaine, despite potential similarities in altering consciousness.
Classical psychedelics interact primarily with layer five pyramidal neurons in the cortex and the claustrum, leading to asynchronous firing and noise in the system. This disruption alters sensory input, allowing the brain to construct new experiences and perceptions internally rather than relying on external sensory stimuli.
"The experience, particularly with psychedelics, is endowed with meaning."
Users of psychedelics often report that these experiences rank among the most meaningful of their lives, indicating a strong salience associated with these altered states. This salience is linked to norepinephrine rather than serotonin, highlighting an unexplored aspect of how these substances create impactful experiences.
The phenomenon of people using substances like DMT often reporting profound experiences that feel more real than ordinary life raises questions about the mechanisms at play. Interestingly, the experiences can differ significantly; while some individuals describe DMT experiences as transformative, others may not recall anything at all yet still report feeling better afterward.
"There’s nothing about the DMT world that resembles anything that we would know in the modern world or in waking normal reality."
The speaker reflects on the surreal nature of experiences induced by various psychedelics, noting that while substances like DMT transport users to alternate worlds, the experiences can feel alien and disconnected from typical reality.
In contrast, substances such as Salvia and Ayahuasca are described as offering experiences that may be more rooted in personal life or relatable narratives, making them "less alien" compared to DMT experiences.
Anecdotes illustrate the bizarre experiences reported by users, such as one individual becoming a plaid pattern on a wall, showcasing the strange yet somewhat grounded perceptions induced by Salvia.
"Sadly, it's impossible to get money to study this sort of thing."
The discussion highlights the significant financial barriers to psychedelic research, with the speaker pointing out that even newly allocated funds, like a proposed $50 million for clinical trials, would be inadequate for meaningful research.
The speaker shares personal experience in drug discovery, emphasizing that large amounts of funding are necessary for even basic phases of clinical trials, illustrating the stark contrast between the funding available and the resources needed for substantial research progress.
"LSD, psilocybin, DMT—they don't bind to the kappa opioid receptor."
There's an intriguing discussion about the discovery of the kappa opioid receptor as a unique target for certain psychedelic compounds, indicating that traditional psychedelics do not interact with this receptor, which was initially surprising to the scientific community.
The impact of this discovery has led to developments of potent analogs of salvinorin A, further expanding the potential for research into therapeutic applications.
"I mentioned it might be possible to design compounds that were ostensibly therapeutic and not psychedelic."
The speaker outlines their interest in developing non-hallucinogenic psychedelics, not merely for the sake of reducing risks for vulnerable populations, such as those predisposed to schizophrenia, but rather as a broader goal within their research.
This line of inquiry began about ten years prior when a collaboration led to the solving of structures for serotonin receptors, which paved the way for using structure-guided drug discovery techniques to pursue therapeutic compounds with fewer psychoactive properties.
A significant funding opportunity arose from DARPA, driven by the need to address psychiatric issues in the military, highlighting the relevance and urgency of innovative therapies that maintain therapeutic benefits without hallucinogenic effects.
"We're starting negotiations… we have patents and everything, so we're negotiating for those too."
The speaker discusses their recent success in securing a grant for research, where they published impactful papers and developed compounds ready for human trials. They are in the process of negotiating the establishment of a company to facilitate this transition and are also focusing on patenting their discoveries.
They express a cautious optimism about the effectiveness of their compounds in human trials, indicating that while they have shown success in mice, it remains uncertain how they will perform in humans.
"We don't know… this is a hypothesis we're testing, basically."
The speaker reflects on the challenge of removing the hallucinogenic properties from psychedelics while retaining their therapeutic benefits, admitting uncertainty about the outcomes of their hypothesis. They note that some individuals believe the hallucinogenic experience is integral to the therapeutic effects.
The research is driven by previous findings that LSD shows bias towards specific signaling pathways. By attempting to create compounds that minimize hallucinogenic activity while maintaining therapeutic efficacy, they hope to provide alternatives for those who may not benefit from traditional psychedelics.
"We try to use structures to help us make the chemical modifications."
The process of developing these compounds involves a trial-and-error approach where chemists synthesize various chemical structures to identify variants that effectively activate receptors in the brain. The modifications focus on fine-tuning their effects on G protein-coupled receptors to optimize therapeutic outcomes.
The scale of this project is significant, with chemists synthesizing approximately a thousand compounds over five years to explore various effects and efficacy in treating conditions such as depression.
"There are people that should not take psychedelics."
The speaker outlines specific groups of individuals, including those with a family history of schizophrenia or bipolar disorder, who should avoid taking psychedelics due to potential risks.
They discuss the rare but concerning phenomenon known as Hallucinogen Persisting Perception Disorder (HPPD), where individuals continue to experience visual disturbances long after using psychedelics. This emphasizes the importance of caution when engaging with psychedelic substances.
"Finding a drug for a target is now not a problem. We've solved that problem. Any target you want, I can make a drug for that target."
The discussion highlights the significant role artificial intelligence (AI) is beginning to play in drug discovery, emphasizing the financial investments and headline news surrounding AI advancements in life sciences.
The speaker, who has extensive experience in studying receptors and drug interactions, notes that AI technologies are already being utilized in their work, mentioning that the field of computational chemistry has been at the forefront of these innovations for decades.
They explain innovations like ultra-large-scale docking, which allows screening a trillion compounds that have never existed in the physical universe, and point out that the hit rate in discovering potential drug candidates is notably high.
"The problem we have is not making the drug. It's choosing the right target for the right drug."
While the technical process of creating drugs has become more efficient, the primary challenge remains in selecting the appropriate molecular targets for drug development, particularly for conditions like depression.
The speaker explains that to develop an effective treatment, one must have a hypothesis regarding which brain protein to modulate, using the example of the 5-HT2A receptor in psychedelics research.
They emphasize that there is currently insufficient training data available to inform AI systems about the therapeutic targets in the human genome, as most of the 26,000 potential targets remain unstudied and unmedicated.
"We don't have sufficient data to train AI for therapeutic targets."
The discussion points out a crucial limitation in drug discovery—the lack of high-quality, comprehensive data concerning therapeutic targets limits the ability to effectively use AI in selecting the right molecular targets.
With only around 2,000 FDA-approved drugs targeting a small fraction of the human genome, the vast majority of targets lack any known functional characteristics or drugs that act upon them.
The speaker notes that to improve therapeutic target selection and enhance drug discovery processes, a better understanding of the biological underpinnings of these unmedicated targets is essential.
