Yukkuri Onega Ishimaas 🧐 @Vathashimo

When you stay "locked in" long enough that the pain flips into pleasure, your body is making its own version of weed. Same chemical family as the THC in marijuana. Researchers nicknamed it the "bliss molecule." People used to credit endorphins for runner's high. Endorphins can't even get into your brain. They're stuck in your bloodstream, too big to cross from your blood into your brain tissue. In 2015, German researchers found what was actually doing the work: your body's homemade weed chemicals. Small. Fat-based. They slip into the brain easily and bind to the same receptors as cannabis. In 2021, the team ran the human version. 63 people on a treadmill for 45 minutes, with a drug in their system that blocks all opioid effects. The high still happened. The cannabis-like system in your body drives this state. Chemistry explains the high. Your brain explains why work feels effortless. Behind your forehead sits a region that runs your inner critic. The voice that judges you. Tracks time. Second-guesses every move. Overthinks. When you go deep into a hard task, this whole region quiets down. A 2008 study at the National Institutes of Health put six jazz pianists in a brain scanner and asked them to make up music on the spot. The scan showed huge chunks of the front-brain going quiet. Inner critic offline. That's the "no thoughts" feeling. Every burst of pain triggers an opposite wave of relief afterward. Every burst of pleasure triggers a small dip. A psychologist named Richard Solomon described this in 1980. With repetition, the pain side weakens. The relief side grows enormous. The first hard run hurts a lot and the relief is mild. The hundredth one barely hurts and the relief is huge. Pain becomes the entry fee for a much stronger pleasure response. Dopamine has its own twist. If you treat the effort as suffering to endure for a payoff, dopamine waits until the payoff and the grind feels heavier the whole way. If the work itself starts feeling like the win, dopamine releases during the grind and your baseline rises. Cold showers work the same trick. One plunge raises dopamine 2.5 times your normal level for two to three hours. DARPA, the US military's research arm, ran a project to teach soldiers to enter this state on demand. They used real-time feedback on the soldiers' brainwaves until they could hit the right pattern. Novice marksmen doubled their accuracy. One catch. Only about 7 in 10 long-distance runners report ever feeling this state, even once. Skill must match challenge. Stakes must feel real. Distractions gone. Feedback immediate. Most lives don't have all four lined up most days. The same brain pattern shows up in meditation, hypnosis, dreaming, jazz solos, and being high on weed. Front of the brain quiet. Deeper systems running. The point where grinding flips into fun is your brain running closer to its actual ceiling.

𝚣𝚎𝚎𝚣 @wtfzeezco

a month ago

when your so locked in and you actually start enjoying it (you've gone insane)

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Patrick OShaughnessy @patrick_oshag

2 months ago

Alex Karnal (@alex_karnal) is the most talented bio and healthcare investor I've ever met. He's spent 20 years in the industry and says 2025 was the single most exciting year he's seen. The start of a once-in-a-lifetime, trillion-dollar revolution in public health. He explains how few people realize we already have the medicines to prevent our deadliest diseases. The problem is that almost no one takes them. There's a population of people born with a mutation that means their bodies don't produce a protein called PCSK9. Their lifetime risk of cardiovascular disease is 88% lower than yours. Pharma turned that genetic advantage into a drug. It's been approved for years, but the number of people taking it is still vanishingly small. Partly because high cholesterol is a silent killer. You feel nothing, right up until you have a heart attack. And partly because the health system makes it punishingly hard to stay on a preventive drug like a PCSK9 inhibitor. In other words, the medicine works, but the system around it doesn't. That's what's starting to change, and in this episode, Alex explains why. We discuss the "health stack" he believes can add a decade to most lives, why oral GLP-1s are breaking every adoption record in pharma, peptides and citizen pharmacology, and what AI is doing to drug discovery. I wish I had an "Alex" for every interesting topic. We've been having versions of this conversation for over five years, and every single one is as clear and as useful as this one. Enjoy! Timestamps: 0:00 Intro 1:00 The State of Modern Medicine 5:00 Designing the Modern Health Stack 12:17 The GLP-1 Inflection Point 19:18 The Biological Mechanisms of GLP-1 30:36 Overcoming Frictions in Healthcare 34:19 Cardiovascular Disease 44:04 Addressing Alzheimer's 47:04 The Future of Cancer 57:33 Drug Discovery 1:05:25 AI and Scientific Super Intelligence 1:14:40 Citizen Pharmacology and the Peptide Movement 1:18:13 Background and Career Journey 1:31:09 Braidwell's Investment Approach 1:33:30 The Kindest Thing

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Yukkuri Onega Ishimaas 🧐 @Vathashimo

2 months ago

@kukreja_abhinav Beat this.... instagram.com/reel/DXExjj0im…

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Yukkuri Onega Ishimaas 🧐 @Vathashimo

2 months ago

@paraschopra Read, Observe, Think

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Anish Moonka @anishmoonka

2 months ago

The woman who inspired Before Sunrise never saw the movie. She died in a motorcycle accident seven weeks before filming even started. Richard Linklater met Amy Lehrhaupt in a toy shop in Philadelphia in 1989. They spent the whole night walking the city from midnight to 6am talking about everything, and he turned that one night into a script. Took him 11 days. The casting search lasted nine months. Jennifer Aniston auditioned before she ever got Friends, and Gwyneth Paltrow tried out too. The role went to Julie Delpy. Amy died on May 9, 1994. She was 24. Linklater kept waiting for her to show up at a screening, maybe tap him on the shoulder and say “Hey, that was our night.” He waited through the premiere. Waited through the sequel nine years later. Didn’t find out she was gone until 2010, when a friend of hers put the pieces together and wrote him a letter. He kept making the films. Brought Hawke and Delpy back every nine years, letting them age on screen in real time. Before Sunset (2004) was shot in 15 days for $2 million. Before Midnight (2013), same thing, 15 days, under $3 million. That last one is dedicated to Amy. All three films together cost $7.5 million to make and earned $61.5 million worldwide, and both sequels got nominated for the Oscar for Best Adapted Screenplay. The entire trilogy cost less than a single Janet Jackson music video that Kahn himself directed. The Library of Congress added Before Sunrise to the National Film Registry earlier this year. It’s now one of 925 films the government considers worth keeping forever. Linklater turned a single night with a woman he’d never see again into an 18-year trilogy. He just didn’t know the “never” part when he started.

Joseph Kahn @JosephKahn

2 months ago

Before Sunrise is unwatchable because it's so good. It's such a beautiful encapsulation of young iPhoneless love, shot on analog film, a nineties time machine of a mysterious Europe that no longer exists, you feel like you are dying as you watch it.