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Huberman Lab

Using Existing Drugs in New Ways to Treat & Cure Diseases of Brain & Body | Dr. David Fajgenbaum

with Dr. David Fagenbaum

Published November 3, 2025
View Show Notes

About This Episode

Andrew Huberman interviews physician-scientist Dr. David Fagenbaum about how many existing FDA-approved drugs can be repurposed to effectively treat diseases beyond their original indications. Drawing on his near-fatal battle with Castleman disease and the work of his nonprofit Every Cure, Fagenbaum explains systemic blind spots in medicine, gives concrete examples of successful drug repurposing, and outlines how patients can better advocate for themselves and navigate disease-specific networks. They also discuss the role of AI in mapping drug-disease relationships at scale, the neuroscience of hope and tenacity, and how Fagenbaum's personal story shapes his mission to ensure that no one misses out on a helpful drug that already exists.

Topics Covered

Artificial intelligence GLP-1 agonists Colorectal cancer Nonprofit organizations Drug repurposing Rare diseases Castleman disease Autoimmune disease Patient self-advocacy Immune system and cytokine storms

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Quick Takeaways

  • There are roughly 4,000 FDA-approved drugs for about 4,000 diseases, yet many of these drugs can effectively treat additional diseases, but the current medical and commercial systems are not designed or incentivized to find and disseminate those new uses.
  • David Fagenbaum survived five near-fatal flares of Castleman disease and ultimately achieved long-term remission by identifying and using an existing drug, sirolimus (rapamycin), off-label based on his own laboratory work.
  • Examples like aspirin for colon cancer recurrence, lidocaine around breast tumors before surgery, thalidomide for leprosy and multiple myeloma, colchicine for heart disease, and immune checkpoint inhibitors for angiosarcoma show that powerful repurposing opportunities already exist but often remain underused.
  • Patients can and should exercise agency by connecting with disease-specific organizations, seeking true experts, asking about off-label or repurposed options, and questioning whether there are promising treatments being used elsewhere.
  • Every Cure uses biomedical knowledge graphs and AI to quantify how likely every approved drug is to treat every human disease, then validates top candidates in the lab and clinic, aiming to systematically match existing drugs to all diseases they can help.
  • The fragmented way physicians consume research-through sporadic papers, conferences, and word-of-mouth-creates large information gaps such that life-saving uses of existing drugs can remain unknown for years or decades.
  • Fagenbaum's athletic background, his experience watching his mother die from glioblastoma, and repeated brushes with death shaped a mindset of relentless, iterative problem-solving and an "overtime" appreciation for life.
  • Huberman describes neuroscience work identifying the anterior mid-cingulate cortex as a key node for the drive to lean into challenges and maintain a strong will to live, which aligns with Fagenbaum's lived "hope-action-impact" circuit.
  • Because 80% of approved drugs are already generic and no longer profitable, no commercial entity is incentivized to systematically explore new indications for most of them, leaving many patients without access to helpful therapies that already exist.
  • Every Cure is structured as a nonprofit so that nearly all newly identified uses of existing drugs can be advanced and shared without creating new monopolies or pricing barriers, focusing on getting effective treatments to patients rather than generating profit.

Podcast Notes

Opening story and core thesis about existing drugs and agency in health

Doctor declares there are no remaining treatment options

David is told by his doctor that all chemotherapies and one experimental drug have been tried and there is nothing more to offer[0:03]
• His family is around his bed crying as the world's expert tells him there are no remaining cell types, pathways, or early-stage therapies to target
David questions the conclusion based on his own treatment history[0:24]
• He notes he has already received seven chemotherapies designed for lymphoma and multiple myeloma that have saved his life multiple times, even if not durably
• He reasons that if seven unrelated chemotherapies helped, there could be an eighth or ninth drug among the ~4,000 FDA-approved drugs that might work too
He commits to a life mission of finding repurposed drugs[1:48]
• He decides in that moment to dedicate however much time he has left-days or months-to searching for an existing drug that could help him and others with his disease
• He articulates a principle: the 4,000 drugs already available should help all patients who can benefit from them, and no one should suffer if a helpful drug is sitting at a local pharmacy

Huberman introduces the podcast, guest, and overarching theme

Huberman introduces himself and the Huberman Lab Podcast[1:23]
• He states he is a professor of neurobiology and ophthalmology at Stanford School of Medicine and that the podcast discusses science and science-based tools for everyday life
He summarizes David Fagenbaum's role and work[1:37]
• David is a professor of translational medicine and human genetics at the University of Pennsylvania
• His work focuses on finding novel cures for rare and common diseases by using existing, human-approved drugs for new purposes
• Huberman notes that most approved drugs affect at least 40 different pathways and mechanisms across the brain and body but are usually approved for just one or two
High-level promise of the episode[2:42]
• David will discuss under-recognized benefits of existing drugs for heart health, cancer, neurodegeneration, and more
• Huberman explains that David's own near-death experience with Castleman disease led him to discover that excellent treatments-and sometimes cures-for diseases labeled incurable can already exist in the drug armamentarium
• David runs a lab and a nonprofit, Every Cure, aimed at identifying and disseminating these overlooked treatments, which have already saved many lives
Huberman frames the blind spot in medicine[3:02]
• He emphasizes that medicine and science are well-intentioned but structurally blind: many effective treatments and cures for "hopeless" diseases exist yet are unknown to even excellent MDs due to how drugs are studied, patented, and categorized
• David's mission includes educating doctors, scientists, and the general public about these hidden opportunities and how he personally used an old medication in a new way to treat his disease

Self-advocacy in health and the idea that answers may already exist

Shift toward patient agency since 2020

Huberman notes increased concern about health even among healthy people[4:09]
• He attributes this to experiences since 2020 that made people realize they must advocate for their own health and learn to navigate medical information themselves
He stresses that doctors are human and that patients can no longer be passive[4:48]
• People are recognizing they are a critical element in their health journey and cannot just accept whatever their local doctor suggests without questions

David on agency beyond wellness and into serious illness

He distinguishes wellness agency from serious disease agency[5:38]
• He observes people readily accept agency regarding sleep, exercise, and diet but often surrender agency once they develop severe diseases like cancer or Castleman disease and default to doing only what their local doctor says
Scale of existing drugs and diseases[6:06]
• He states there are about 4,000 FDA-approved drugs for roughly 4,000 diseases, but laboratory and clinical evidence shows many drugs can be beneficial in additional diseases beyond their labeled uses
• Despite this, the system is not structured to systematically find new uses for old medicines, which is the gap his work targets

Concrete steps patients can take to exercise agency

Connect with disease organizations[6:30]
• He advises patients to identify and connect with the main advocacy or disease organization for their condition (e.g., Castleman Disease Collaborative Network, ALS Association, Michael J. Fox Foundation for Parkinson's)
• Such groups often know about treatments or off-label drug uses being tried in different parts of the world that may not be widely known
Find and question leading experts[6:39]
• He urges patients to locate the global or national experts for their disease and, if possible, travel to see them in person
• Even after an expert prescribes a treatment, patients should ask whether there are additional potential options, including drugs used elsewhere or for related conditions

Examples of drug repurposing and systemic blind spots

Aspirin's underused roles

Beyond pain relief and heart attack prevention[6:53]
• David notes aspirin is widely known as a pain reliever and as a blood thinner to reduce heart attack risk
• He adds that aspirin also reduces risk of colon cancer recurrence, especially in patients whose cancers carry mutations in the mTOR pathway
• Despite being inexpensive and widely available, aspirin's use for colon cancer recurrence prevention is not standard for all eligible patients

Viagra, Cialis, and unexpected beneficial "side effects"

Viagra evolved from heart disease drug to multiple indications[7:41]
• Viagra was initially developed for heart disease but became known for treating erectile dysfunction
• David points out it was also repurposed for a rare pediatric lung disease in which children lacked sufficient blood flow to their lungs; Viagra restored lung blood flow and allowed them to live full lives
• This pediatric lung use was discovered early in the drug's patent life, which enabled strong commercial support to bring it forward
Cialis and formulation stories[8:09]
• Huberman notes that Cialis (tadalafil) was initially developed to influence prostate circulation and health, with later appreciation of its sexual function effects

Polypharmacology: drugs hit many targets, but we use only a few

Most drugs bind many proteins beyond their primary target[8:31]
• David says the average small-molecule drug binds 20-30 different proteins in the body, even though we typically talk about a drug as if it "does one thing"
• Unless a company chooses early on to develop a drug for an additional disease, these extra actions often go unexplored, especially after patent expiry

Lidocaine injection before breast cancer surgery

Large Indian study shows major mortality reduction[9:40]
• Every Cure identified data on lidocaine, commonly used as a local anesthetic, showing unexpected survival benefits when injected around breast tumors before surgery
• In a 1,600-patient trial in India, women with localized breast cancer who received peritumoral lidocaine 8-10 minutes before surgery had a 29% reduction in 5-year mortality compared to those who did not receive it in that way
• Lidocaine is already widely used during surgery (at incision sites) and is inexpensive, yet this specific pre-tumor injection practice has seen very little global uptake despite publication in a major oncology journal
Why lidocaine's benefit hasn't spread[10:40]
• Lidocaine has been generic for decades; multiple companies make it, leaving only pennies of profit per injection and no company strongly incentivized to promote this specific practice to surgeons
• David emphasizes he does not think anyone is hiding lidocaine, but rather that no entity is incentivized to champion its repurposed use or ensure it is included in guidelines
• Every Cure feels a responsibility to fully evaluate lidocaine's mechanism and evidence before encouraging broad adoption despite the promising mortality reduction and low downside

Drug company incentives, patents, and gaps in repurposing

How patent cliffs shape drug development behavior

Huberman describes the patent cliff and repurposing for profit[14:22]
• He recounts learning that companies with blockbuster drugs nearing patent expiration are highly incentivized to find new uses or formulations to extend exclusivity and keep generics at bay
• He frames two "dark sides": delayed entry of cheap generics and a tendency to seek new indications for existing molecules instead of developing entirely new drugs
David clarifies what is and isn't explored[15:01]
• He explains that near the patent end, companies often alter dose or formulation to stay in the same disease area, rather than exploring new diseases for that drug
• Once drugs go generic, essentially all formal R&D for new indications stops, even though many could help additional diseases
• He notes that among 4,000 FDA-approved drugs, 80% are generic, yet there are about 14,000 diseases with no approved treatment at all
• He often walks past pharmacies thinking about how many drugs on the shelves are used for one condition but could help many more patients if their other effects were understood and utilized

DATA2: a rare stroke syndrome and a delayed repurposing insight

Tragic natural history of DATA2[18:58]
• DATA2 is a rare condition where children have a mutation causing dozens of strokes from birth through adolescence, often dying in their teenage years from cumulative damage
Serendipitous use of a TNF inhibitor[20:28]
• About 20 years ago, a doctor treating both a DATA2 patient and a vasculitis patient gave the vasculitis patient a TNF inhibitor and had leftover drug in the vial
• He decided to try the TNF inhibitor in the DATA2 child who was having many strokes; the child stopped having strokes, and subsequent DATA2 patients also responded
Years of lost lives before knowledge spread[20:12]
• Despite this success, roughly a decade passed before the insight became more widely known while hundreds to thousands of children worldwide continued dying from DATA2
• A physician-father, Chip Chambers, with two children with DATA2, later discovered the TNF inhibitor reports and, with David's help, compiled data, showing that starting children on TNF inhibitors stops their strokes
• David finds it heartbreaking that "the world knew" in the sense that one doctor had the knowledge, but "the world didn't know" because the system failed to disseminate a life-saving therapy

Need for better medical knowledge systems and AI-based mapping

Huberman's vision for symptom and family-history driven databases

Current online search experiences are inadequate and alarming[23:08]
• Huberman points out that typing symptoms like "swollen lymph node in armpit" into general search engines typically yields a list of dire diagnoses without helpful triage or nuance
Proposed AI-enabled medical navigation tool[23:44]
• He imagines a database where individuals can input family history (e.g., ages and causes of death of parents and grandparents) and current symptoms, and receive AI-informed suggestions about likely conditions and existing drugs or over-the-counter molecules that might help
• He emphasizes that such a system should be grounded in PubMed and other scientific repositories, with cautionary context, and should help people identify the best disease organizations and clinicians to contact

Every Cure's use of biomedical knowledge graphs and AI

David describes their all-versus-all scoring approach[24:59]
• Every Cure builds biomedical knowledge graphs capturing what is known about human biology, drugs, and diseases, and uses AI/machine learning to quantify how likely each drug is to treat each disease
• They then prioritize top-ranking drug-disease matches, of which they currently have nine active programs, and run laboratory experiments and clinical evaluations with the goal that many will prove effective

Further repurposing examples: thalidomide, pembrolizumab, creatine vs overlooked drugs

Thalidomide: from tragedy to lifesaving cancer drug

Original use and birth defects crisis[25:01]
• Thalidomide was originally used as an anti-nausea drug for pregnant women but caused severe birth defects, such as babies being born without limbs, leading to its withdrawal
Later repurposing for leprosy and multiple myeloma[25:16]
• About 20 years later it was found effective for leprosy and subsequently received FDA approval for that indication
• It was later approved for multiple myeloma, a hematologic cancer; its anti-angiogenic effect (inhibiting blood vessel growth) underlies both its therapeutic action in cancers and its teratogenic birth defects
• David notes that if the multiple myeloma use had been discovered after thalidomide went generic, it likely would not have been developed as a myeloma drug because no patent incentive would exist

Pembrolizumab for angiosarcoma: a simple literature search with huge impact

Identifying a checkpoint inhibitor opportunity[27:17]
• In 2016, a patient with metastatic angiosarcoma whose doctors believed he was out of options approached David's lab
• They conducted a straightforward PubMed search for angiosarcoma treatments and found a 2013 paper where four of five angiosarcoma tumors showed high PD-L1 expression, suggesting susceptibility to PD-1 inhibitors like pembrolizumab
Clinical response and change in practice[26:44]
• Despite the 2013 paper, no one had trialed a PD-1 inhibitor for angiosarcoma by 2016; David's team arranged for the patient (Michael) to receive pembrolizumab off-label, and he responded remarkably well
• Subsequent use in more patients revealed about an 18% response rate, transforming a previously uniformly fatal cancer within a year into one where ~20% of patients now live beyond a year
• Michael himself has been in remission for nine years and recently walked his daughter down the aisle, illustrating the life-changing potential of connecting such "breadcrumbs"

Creatine's publicity vs under-discussed repurposed drugs

Huberman contrasts hype around supplements with silence on drugs like aspirin[32:41]
• He notes that creatine is widely discussed for strength, cognitive support, and use across age groups, even though its cognitive benefits are modest
• By contrast, powerful repurposing data for drugs like aspirin (e.g., reducing colon cancer recurrence and heart attacks) and others rarely enter public discussion, partly due to fears people will self-prescribe without supervision

Colchicine, Bachman-Bopp syndrome, and broader repurposing logic

Bachman-Bopp syndrome and DFMO from African sleeping sickness

Severe baseline condition[34:24]
• Bachman-Bopp syndrome is an ultra-rare disorder where children are born with high levels of an enzyme David calls OCE1, leading to feeding-tube dependence and being bed-bound or wheelchair-bound
Repurposed treatment and functional gains[34:31]
• A drug developed for African sleeping sickness, DFMO, covalently binds the overactive enzyme and, if started early, can allow affected children to have feeding tubes removed, sit up, and even play with siblings
• Only about 20 children with Bachman-Bopp have been described in the literature, implying likely hundreds in reality; David wants to ensure every child with the condition is found and treated with DFMO

Colchicine from gout remedy to heart disease prevention

Ancient use in gout and modern hypothesis[35:57]
• Colchicine has been used for gout for centuries, possibly millennia, and has anti-inflammatory properties
• A researcher hypothesized it could reduce heart attack risk due to its anti-inflammatory effects and other properties, especially in those who had already had a heart attack
Dose tweaking to enable expensive trials[37:06]
• Because colchicine had been around so long and was generic, there was no straightforward way to fund large, long-duration heart-disease prevention trials, which require following patients for years
• Researchers changed the dose, creating a slightly different formulation, which allowed for new intellectual property and justified expensive trials that showed substantial reduction in heart disease risk in people with prior heart attacks and especially those with diabetes
• It is now FDA-approved for a specific heart disease subpopulation, but David notes that without the reformulation workaround, the data might have remained obscure and underutilized

Personal backstory: mother's glioblastoma and lessons in agency

Mother's diagnosis and impact on an 18-year-old

From football dream to confronting brain cancer[41:30]
• At 18, David was a freshman and quarterback at Georgetown University, living his childhood dream of playing Division I football
• His father called to say his mother had glioblastoma, a uniformly fatal brain cancer, which shifted his priorities from sports to her illness
• Watching her 15-month battle convinced him to dedicate his life to finding treatments for patients like her, a commitment he verbalized to her just before she died
"Unconditional love" as guiding phrase[42:58]
• When he promised to work on treatments, his mother, who could barely speak, said the words "unconditional love," which he interpreted as an endorsement of his path and a standard to live by

Brain surgery moment: Chiquita Banana Lady

Awake surgery and fear of personality changes[43:34]
• His mother underwent a surgery where she was awakened during tumor resection so surgeons could monitor speech and function, especially since it was on the left side
• After surgery, David and his family anxiously approached her bed, unsure if she would still be herself given the amount of brain tissue removed
Humor as reclaiming agency[43:40]
• With her head bandaged and a bulb collecting fluid, she pointed to her head and joked, "Chiquita Banana Lady," making her family burst into laughter
• For David, this moment exemplified taking agency back from a horrible disease by finding humor and showing her personality despite immense adversity

Castleman disease onset, near-death episodes, and systemic blind spots

Initial onset and diagnostic odyssey

From delivering babies to multi-organ failure[46:43]
• As a third-year med student at Penn, just after completing an OB/GYN rotation and delivering babies, David developed enlarged neck lymph nodes, extreme fatigue, abdominal pain, and ankle swelling
• Within weeks he became so ill he went from taking a med school exam to stumbling into the emergency department, where labs showed his liver, kidneys, and bone marrow were failing
• He was hospitalized, rapidly deteriorated, suffered a retinal hemorrhage causing temporary blindness in one eye, gained ~100 pounds of fluid due to organ failure, and required daily red cell and platelet transfusions plus dialysis
Receiving last rites before diagnosis[48:25]
• Over 11 weeks with no clear diagnosis, doctors debated lymphoma vs autoimmune disease; during a particularly dire period, a priest administered last rites when he was only 25
Final diagnosis: Castleman disease[48:54]
• A pathologist examining a lymph node, initially suspected to be lymphoma, identified features consistent with Castleman disease, an atypical lymphoproliferative disorder with autoimmune-like aspects
• In his case, the immune system became hyperactivated and attacked his vital organs via high levels of cytokines, explaining the multi-organ failure

Could high-drive lifestyle have contributed?

Mouse study linking sleep deprivation to cytokine storms[49:03]
• David references a Cell paper where severely sleep-deprived mice died from cytokine storms, including excess interleukin-6, and blocking certain cytokines extended their lives
• He sees this as a mechanistic link between extreme sleep deprivation, immune dysregulation, and potentially fatal inflammatory responses, resonating with his own grueling work schedule before illness
Known link between stress and autoimmune flares[50:51]
• He notes strong evidence that among people already diagnosed with autoimmune diseases, stress and sleep loss can trigger flares, even though it's less clear whether they cause the diseases initially

Missed opportunity: tocilizumab in Japan

Existing Castleman-targeted drug unknown to his doctors[51:16]
• At the time of his first episodes, there was no Castleman-approved treatment in the U.S., but a drug called tocilizumab had been developed and approved for Castleman disease in Japan
• The U.S. doctors did not know to try it; instead, they gave chemotherapy, which fortunately saved his life but missed a potentially targeted option already in use abroad
Kazu's self-injection story[52:15]
• David recounts that Dr. Kazuyoshi (Kazu) Zak, who discovered tocilizumab, reportedly first had it injected into himself to ensure its safety before giving it to patients, at a time when monoclonal antibodies were new
• Kazu later used it successfully in Castleman patients in Japan, then it was repurposed for rheumatoid arthritis and other autoimmune diseases in the U.S., but it did not work in David's particular case

Seven chemotherapy regimen and feeling better on chemo

Combination chemo as a paradoxical relief[53:22]
• After tocilizumab failed, David received an aggressive combination of seven chemotherapies (e.g., adriamycin, cytoxan, etoposide, Velcade, thalidomide, rituxan), typically among the harshest in oncology
• Because the drugs suppressed his overactive immune system that was producing the damaging cytokines, he actually felt better with each dose, despite the toxicity of the regimen
• He eventually became well enough to leave the hospital after six months, followed by six months of medical leave to rebuild his strength

Systemic issues: physician information gaps and the "Santa Claus theory"

How much literature do practicing physicians actually consume?

Piecemeal, random exposure to research[58:01]
• David explains that practicing physicians have limited time and generally learn about new findings through sporadic reading, occasional conferences, and papers colleagues send them
• No doctor can systematically review millions of papers, or even all relevant ones for their disease areas, resulting in "watered-down" summaries and inconsistent adoption of findings

Second opinions and the myth of omniscient expertise

Why second opinions often differ[58:34]
• He notes that what are called "second opinions" are still opinions, influenced by each doctor's partial knowledge and experience, which is why they sometimes disagree with first opinions

Santa Claus theory of civilization

Idealized view vs reality[59:19]
• As a medical student, David imagined rooms full of scientists and doctors working together like Santa's elves in a workshop, ensuring that as soon as a drug could be discovered, it would rapidly reach patients
• His experience with Castleman disease showed him this is not how reality works; there are not coordinated teams systematically solving each problem at the pace patients need

Relapses, self-directed lab work, and discovering sirolimus (rapamycin)

Relapse despite experimental drug and decision to self-investigate

Fourth relapse and being told options are exhausted[1:04:26]
• Back in med school on an experimental drug similar to tocilizumab, David relapsed about a year later, returning to the ICU with multi-organ failure for a month
• The global expert told him and his family that all options had been tried and there was nothing more to do, prompting a period of intense grief
Logical pivot: we haven't tried all 4,000 drugs[1:04:52]
• Even as he heard "there is nothing," he reasoned that if seven chemotherapies not designed for Castleman had repeatedly saved his life, there could be an eighth or ninth drug among the thousands approved for other indications
• He committed on the spot to dedicating whatever time remained to identifying an existing drug that could help him and others with his disease

Collecting his own samples and learning lab techniques

From MD/MPH to bench science novice[1:05:40]
• He began storing his blood samples every couple of weeks and persuaded a colleague to lend him lab space, even though he had no formal lab training
• He used flow cytometry to characterize immune cells and serum proteomics to measure ~1,000 proteins in his blood, searching for actionable abnormalities
• He helped found the Castleman Disease Collaborative Network to accelerate research and coordination around the disease

Fifth relapse and the "overtime" experience

Failed initial repurposing attempts and writing a will[1:07:10]
• Based on his early lab work, he hypothesized that cyclosporine and IVIG might help and tried both, but neither worked; he relapsed again, his fifth near-death episode
• Convinced he was dying, he wrote his will on a piece of printer paper, cried with his fiancée Caitlin, and felt deep disappointment that his attempts had failed
Surviving and feeling like life is in overtime[1:08:48]
• After receiving a very high dose of etoposide, he surprisingly began to wake up two days later, experiencing what he calls "overtime"-a sense that every additional second is extra, precious life
• As soon as he regained some consciousness, he immediately started giving instructions to his family to move his stored lymph node and serum samples to a lab in Philadelphia so he could take another shot at finding a treatment

Discovering mTOR overactivation and proposing sirolimus

Immunohistochemistry reveals mTOR activation[1:10:05]
• Three weeks after discharge, he analyzed a resected lymph node using immunohistochemistry staining for mTOR activation and found it was "blazingly" positive
Sirolimus as a repurposed option[1:09:40]
• He brought the data to his doctor and suggested trying sirolimus (rapamycin), an mTOR inhibitor approved for organ transplant rejection, which had never been used for Castleman disease
• The doctor agreed and prescribed sirolimus at the standard transplant dose, far higher than the low, intermittent doses some people discuss for longevity
• In the 3.5 years before sirolimus, David almost died five times; since starting sirolimus, he has been in remission for about 11 and three-quarter years

Athletic background, resilience tools, and "overtime" mindset

How football prepared him mentally and physically

Long-term goal pursuit and tracking[1:13:25]
• From age eight, he set a specific goal to become a Division I college quarterback and tracked his throwing distance, accuracy, 40-yard dash, and mile times on poster boards over ten years
• He sees this decade-long, metrics-driven pursuit of a clear mission as training for the kind of sustained effort required to solve a complex medical problem
Pain tolerance and getting back up after losses[1:14:13]
• Playing at Georgetown, which lost many games, taught him to get back up and continue fighting after setbacks
• Physical hardships in football-broken collarbones, broken hands, and punishing drills like "rolling" until players vomited-taught him to endure pain, which later helped him tolerate the excruciating pain of ICU fluid overload

Three psychological tools he used in the ICU

1) Clear vision for the future[1:16:10]
• He held a vivid image of a future life with his partner Caitlin and a career discovering drugs for patients in memory of his mother, which made present suffering feel meaningful
2) Drawing strength from family presence[1:16:12]
• He felt literal strength in his hands from his father and sisters holding them, especially his sister Gina, who at one critical moment kept telling him "just breathe, Dave" when he was tempted to slow his breathing and let go due to pain
3) Breaking suffering into manageable time units[1:16:15]
• Instead of contemplating six continuous months of extreme pain-which he feels he could not have endured-he focused on surviving the next minute, hour, or day, and repeating that process

Scaling repurposing: business school, Every Cure, and AI-driven programs

From medical school to business school and lab leadership

Why he studied business[1:23:40]
• After med school, he attended business school because he realized the biggest barriers to medical progress were often organizational-collaboration, resource allocation, and strategy-rather than purely scientific
• He actually discovered sirolimus as his own treatment while in business school, then later joined the Penn faculty and established a lab initially focused on Castleman disease

Applying sirolimus to other Castleman patients

Case examples from Brazil, New Zealand, and Philadelphia[1:24:25]
• They first used sirolimus in Castleman patients in Brazil and New Zealand, then in a 13-year-old boy named Joey at Children's Hospital of Philadelphia who was near death
• Joey responded dramatically, turning around from being critically ill to now being a college student at Temple University, which deeply impacted David because he observed the turnaround firsthand

Ruxolitinib and other Castleman repurposings

Kyla's case with a myelofibrosis drug[1:25:22]
• His lab identified that a drug used for myelofibrosis, ruxolitinib, might help Castleman disease, and recommended it for a girl named Kyla in Chicago whose disease was unresponsive to other therapies including sirolimus
• Ruxolitinib worked extremely well; she is now in college at Marquette University and plans to become a nurse

Broad expansion beyond Castleman: 14 repurposed drugs

From Castleman to angiosarcoma and beyond[1:25:28]
• Building on successes with Castleman, they applied similar logic to other diseases such as angiosarcoma (with pembrolizumab) and, over 11 years, identified 14 drugs successfully repurposed for diseases they were not originally designed to treat

Founding Every Cure to systematize repurposing with AI

From one-company AI to all-drugs-for-all-diseases AI[1:26:42]
• Co-founder Grant Mitchell had been using AI to help individual drug companies find new uses for their own medicines; David and his co-founders asked what if the same approach could be applied across all drugs and diseases
• They launched Every Cure three years ago with the aim of scanning all 4,000 approved drugs against all ~18,000 human diseases to find and validate the highest-value repurposing opportunities

Hail Mary cases: Al with Castleman and Joseph with POEMS syndrome

Al in Vancouver: TNF inhibitor guided by AI ranking[1:28:00]
• For a Castleman patient named Al in Vancouver, refractory to prior therapies, Every Cure's machine learning ranked a TNF inhibitor as the top candidate drug
• Based on additional lab data about CD4+ T cells producing too much TNF, they recommended adalimumab; Al responded very well and has been doing well for two years, with the case published in the New England Journal of Medicine
Joseph with POEMS: applying myeloma regimens[1:28:51]
• A patient named Joseph with a rare cancer called POEMS syndrome was near death in intensive care and about to be taken off life support; his girlfriend Tara reached out to Every Cure
• Recognizing biological similarities between POEMS and multiple myeloma, David's team recommended three standard myeloma drugs; although doctors initially feared chemotherapy might kill him, they agreed to try because he was otherwise terminal
• Joseph responded extremely well and has been in remission for over a year and a half

Balancing innovation with safety and the role of mechanism

Concerns about off-label experiments causing harm

Huberman raises historical examples of harm[1:31:42]
• He recalls a fatal gene therapy case that set the field back for years and a contaminated tryptophan batch causing illness and death, leading to its temporary removal from the market
• He notes that a single death or severe adverse event can freeze entire therapeutic areas, making caution around repurposing understandable

Every Cure's safeguards and focus on evidence

Avoiding speculative Hail Marys where possible[1:32:55]
• David says they try to avoid Hail Mary use of drugs without strong evidence, because speculation can cause harm as easily as benefit
• Their process is to use AI to highlight promising matches, then do rigorous lab work, clinical trials, and careful evidence review before actively advocating a new use
Physician-patient decision-making remains central[1:33:26]
• David emphasizes that in all cases there is a treating physician making the prescription decision with the patient; Every Cure's role is to provide data and options, not to replace that relationship

Repurposing for health optimization and blurred natural-drug lines

Examples of clinicians using drugs preventively for themselves

Nicotine, lithium, and neuroprotection anecdotes[1:37:20]
• Huberman mentions an MD-neuroscientist colleague who chews multiple pieces of nicotine gum daily, believing nicotine (distinct from smoking) helps protect dopaminergic and cholinergic neurons and thereby reduces risk of Parkinson's and Alzheimer's
• He also cites psychiatrists who periodically take low-dose lithium for perceived neuroprotective benefits based on their reading of the literature, though not prescribing it to patients for that purpose

David's view on preventive repurposing and GLP-1s

Need for rigorous data on prevention uses[1:38:48]
• David agrees that repurposing logic can apply to prevention and health optimization but stresses that evidence is often limited and must be strengthened
GLP-1s as an emerging example[1:40:10]
• He notes emerging evidence that GLP-1 receptor agonists, beyond their metabolic effects, may improve Parkinson's symptoms and reduce risk of Alzheimer's disease and breast cancer among people taking them

Bioprospecting and natural origins of drugs

Rapamycin from soil on Rapa Nui[1:40:22]
• Rapamycin (sirolimus) was discovered in a soil sample from Rapa Nui (Easter Island) collected by a Wyeth researcher systematically sampling Pacific island soils for bioactive compounds
• Initially thought to be an antifungal, rapamycin turned out to be a poor antifungal but an excellent immunosuppressant, and research into its effects helped elucidate the mTOR pathway
• David underscores that many potent drugs, including the one keeping him alive, are naturally occurring and discovered via bioprospecting, blurring boundaries between "natural" supplements and pharmaceuticals

Hope-action-impact circuit and its neural basis

David's hope-action-impact loop

Description of the circuit[1:47:12]
• He describes a three-step loop: hope for a future outcome, taking action based on that hope, and seeing some impact, which in turn fuels more hope and further action
• He found this pattern crucial in his own life, whether running experiments on his blood to find a drug or helping his child with a health issue

Huberman's neuroscience explanation: anterior mid-cingulate cortex

Stimulation experiments in awake patients[1:47:29]
• Huberman describes work by neurosurgeon Joe Parvizi who stimulated the anterior mid-cingulate cortex (aMCC) in awake patients and elicited sensations of an impending challenge plus a strong urge to lean into it
• Moving the electrode even a millimeter changed the effect, suggesting a specific role of the aMCC in tenacity and willingness to confront challenges
Association with super-agers and depression inverse[1:48:19]
• He notes that older adults who maintain unusually strong cognitive and functional capacities ("super-agers") often show preserved volume in the aMCC and report a strong will to live
• He contrasts this with major depression, characterized by low positive anticipation and low belief that actions can change outcomes, which aligns with reduced functioning in these circuits
• Huberman speculates that David's aMCC is likely highly robust, possibly strengthened by his early, sustained goal pursuit in football and later problem-solving in medicine

Practical engagement with Every Cure and funding model

How individuals and experts can contribute

Submitting ideas and data[1:53:01]
• David invites anyone to visit everycure.org/ideas to share information about off-label uses they have experienced or research-driven hypotheses about drugs that might work in new diseases
• His team will compare submissions to their AI predictions and, if promising, consider moving them forward
Expert network and public awareness[1:54:04]
• Experts in specific disease or biology areas can sign up so that when Every Cure identifies a candidate drug for their domain, they can advise on its plausibility and clinical context
• He encourages people to raise awareness via social media, sharing his TED talk, and supporting the nonprofit financially to fund costly clinical trials

Funding sources and non-profit nature

Current funding mix[1:54:02]
• About half of Every Cure's funding comes from the U.S. government through ARPA-H, and about half from individual donors
No profit motive for most repurposed uses[1:55:12]
• He explains that in nearly all cases they pursue, the repurposed use will involve the same dose and formulation of an existing drug, with no new intellectual property or profit opportunity
• In rare cases where a different formulation (e.g., brain-penetrant) or dose is needed, a company might be spun out, but the overarching model is nonprofit and patient-focused

Closing reflections on self-advocacy and system change

Huberman's summary of practical advice

For healthy people and those with disease[1:55:27]
• He reiterates that healthy individuals should safely explore options, understand what is known and unknown, and recognize that helpful drugs may exist beyond conventional prescriptions
• For those with illness, he emphasizes finding robust disease-specific organizations, identifying multiple such groups, and discovering who the best experts are in the world for that condition
Acknowledgment of David's unique contribution[1:56:20]
• Huberman thanks David for transforming personal hardship into work that helps many others and expresses interest in hosting him again to explore additional topics

Lessons Learned

Actionable insights and wisdom you can apply to your business, career, and personal life.

1

Many life-saving treatments already exist within the set of approved drugs, but structural blind spots and lack of incentives mean patients and even top clinicians often don't know about them-so systematic search and self-advocacy are essential.

Reflection Questions:

  • • What serious health risks or conditions in my life or family might warrant a deeper search into existing but lesser-known treatment options?
  • • How can I, or someone I care about, more proactively engage disease organizations and true experts rather than relying solely on the first opinion we receive?
  • • What specific question about alternative or off-label treatments will I bring to my next medical appointment to ensure I'm not missing a viable existing option?
2

Relying on the assumption that "the system" is already optimizing treatments for every disease is dangerous; individuals and organizations must build and use better tools-like AI-driven knowledge graphs-to connect scattered evidence into actionable therapies.

Reflection Questions:

  • • Where in my work or personal life am I assuming that existing systems are already doing the optimal thing, instead of checking whether key information is fragmented or outdated?
  • • How might using modern tools like structured databases or AI (even at a basic level) change the way I gather and synthesize information for important decisions?
  • • What is one recurring problem I face that could benefit from systematically mapping connections between pieces of information, rather than treating each data point in isolation?
3

When facing overwhelming challenges, breaking them into a hope-action-impact loop-anchored in a concrete vision of the future and very short time horizons-can convert despair into sustained, productive effort.

Reflection Questions:

  • • What meaningful future outcome do I care about enough to use as an anchor when current circumstances feel unbearable or confusing?
  • • In a tough situation I'm dealing with now, what is the smallest concrete action I can take in the next 24 hours that might create even a tiny positive impact?
  • • How will I regularly review and update the link between my longer-term hopes and the specific actions I'm taking, so that each small impact feeds back into renewed motivation?
4

Cross-domain thinking-looking at drugs, tools, or solutions developed for one problem and asking whether they might apply to a nearby but different problem-can unlock high-value opportunities that siloed experts routinely miss.

Reflection Questions:

  • • Where in my field or life do I see two problems that share similar underlying mechanisms or patterns, but are treated as totally separate domains?
  • • How could I deliberately expose myself to research or practices from adjacent fields to spark ideas about repurposing existing tools or approaches?
  • • What is one existing solution I already understand well that I could consciously test or explore in a different, but related, context this month?
5

Strong, collaborative support networks-family, colleagues, and mission-driven organizations-radically improve the odds of navigating crises successfully compared to going it alone.

Reflection Questions:

  • • Who are the specific people or groups I would want in my corner if I or someone close to me faced a major health or life crisis tomorrow?
  • • How can I invest now in being a reliable supporter for others, so that mutual trust and connection are already in place before a crisis hits?
  • • What concrete step can I take this week to strengthen my ties with a disease organization, professional community, or personal network that might matter in a future challenge?

Episode Summary - Notes by Drew

Using Existing Drugs in New Ways to Treat & Cure Diseases of Brain & Body | Dr. David Fajgenbaum
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