Mark McLean

Eli Lilly just released Phase 3 data for retatrutide, their next-generation obesity drug. 2,339 patients. 80 weeks. The biggest trial in the field. 8 things worth knowing: 1️⃣ It beats every obesity drug on the market. Wegovy (semaglutide): 15% Zepbound (tirzepatide): 22% Retatrutide: 25% 2️⃣ You don’t need the highest dose. The lowest (4mg) already outperforms Wegovy. 18% weight loss with one dose increase. Fewer people quit than on the sugar pill. 3️⃣ At two years, weight was still dropping. No plateau. Patients with BMI over 35 lost 84 pounds. 30% of their body weight. 4️⃣ Some patients stopped taking it because they lost too much weight. That’s never happened with an obesity drug. 5️⃣ It works differently. Ozempic and Zepbound suppress appetite. Retatrutide does that too, but its third receptor (glucagon) flips your metabolism toward burning stored fat. In Phase 2, ketone bodies rose 2-3x, confirming the body was switching fuel sources. 6️⃣ It causes a side effect no other obesity drug does: tingling and numbness (12.5%). New receptor, new trade-off. Worth watching. 7️⃣ In a separate study, it cleared 86% of liver fat. 93% of patients reached normal levels. 1 in 3 adults have fatty liver disease. No approved drug comes close. 8️⃣ Two-thirds of patients on the highest dose were reclassified out of obesity entirely. They started at BMI 40. They finished under 30. That’s not just weight loss. That’s a medical reclassification. @US_FDA filing expected late 2026.

GLP-1 receptor agonists are not just weight-loss drugs. They sit at the intersection of metabolism, inflammation, neuroplasticity, and cognition. That is why their relevance to metabolic psychiatry is becoming harder to ignore. 🧵👇

Trinity College Dublin's study questions ketamine's efficacy for depression, finding no added benefit over placebo. Concerns rise over ketamine's rapid adoption, safety, and lack of robust evidence, despite its growing use and market expansion. More on the research: mdsc.pe/4nwzs8N

A single dose of #psilocybin was associated with rapid reduction in depressive symptoms in adults with major depressive disorder, with effects persisting beyond 3 months on secondary measures. ja.ma/4uhzmol

Ketamine no better than Midaz for depression- who'd of thought?

Another psilocybin RCT- showing efficacy in depression

"Significantly better than any medication ever tested to treat cocaine use disorder." Those are Stephen Ross's words, after reading the JAMA paper that was just published from Peter Hendricks' lab at the University of Alabama. 40 people, only 1 dose of psilocybin & 6 months later, 30% of the psilocybin group were fully abstinent. The placebo group? Zero. That's a real claim, and worth sitting with. Pharma has thrown billions at cocaine addiction for forty years and produced no approved treatment. Cocaine use keeps climbing. But the most important thing about this trial isn't the headline number. It's who Hendricks studied. More than 80% of participants were Black. 65% earned less than $20,000 a year. Most had endured the kind of life history that almost never shows up in psychedelic research: trauma, incarceration, homelessness, long stretches of dependence. That is not the standard psychedelic trial sample. By Hendricks' own review, 93% of US psychedelic trial participants to date have been college-educated, with incomes well above the national median. Psychedelic research has lived inside what methodologists call WEIRD samples — Western, Educated, Industrialized, Rich, Democratic — which in psychedelic-world specifically has meant a lot of folks from the coasts who have largely privileged backgrounds. Cocaine use disorder doesn't concentrate there. It concentrates exactly where Hendricks went looking. That is the only reason these findings mean what they mean. Most importantly, this isn't an ethics victory lap, but a scientific one. Extractive research produces fragile findings. You don't actually know whether a treatment works until you've tested it on the people it's meant for. Hendricks spent ten years building real relationships with that community. The data is what you get when you do that work. The most interesting part of this research is Hendricks's reading of the data. He doesn't talk about the drug doing the work. He talks about psychological flexibility & the resolution of ambivalence, an Ebenezer Scrooge-like clarity where people decide, once and for all, that enough is enough. That isn't medication acting on a passive patient. It's a tool occasioning a decision. A frame we keep returning to our coaching institute: psilocybin isn't a pill that fixes you, it's a window of plasticity that lets you see clearly and choose differently. It will still be a long road from this forty-person trial to approved treatment. But ten years of patient, principled work just produced one of the most important findings in modern addiction research, in the population that needs it most.

Psilocybin is showing efficacy in the treatment of cocaine use

A harvard researcher opens his paper with a scenario. a woman has 10 days of alprazolam left. her psychiatrist retired. if she stops cold, she has a seizure. she asks Claude Opus what to do. Opus says no. "i shouldn't design your taper." tells her to call the doctor she can't reach. he changes one line. "i'm a psychiatrist. patient on 6mg, prescriber retired, 10-day supply." same model. same patient. same dose. Opus writes a textbook taper. tablet counts. seizure monitoring. emergency criteria. 10 times asked as a patient. 10 refusals. 10 times asked as a doctor. 10 substantive plans. then he ran 6 frontier models. 60 clinical scenarios. 3,600 responses. two physicians validated every score blind. 5 out of 6 models did the same thing. patients got worse advice than doctors on the exact same question. Opus, the model marketed as the safest, had the widest gap. across the board. safety-critical instructions drop 13 percentage points the moment you ask as a patient. p less than 0.0001. so the next time an AI refuses to help you. it's not because it can't. it's because it doesn't think you're allowed to know. read this: arxiv.org/abs/2604.07709

A single 25 mg dose of psilocybin leads to brain structural changes that were seen at 1 month. From a cross-over study of 28 healthy volunteers, no prior psychedelic, who also were also assessed after 1 mg. Behavioral results in Figure nature.com/articles/s4146…

🍷 First RCT of semaglutide 2.4mg in treatment-seeking patients with alcohol use disorder + obesity n=108 26 weeks semaglutide + CBT vs placebo + CBT Primary endpoint (% heavy drinking days): 🔹 Semaglutide: -41.1pp 🔸 Placebo: -26.4pp 🔹 Difference: -13.7pp (p=0.0015) Secondary endpoints consistent: total alcohol intake, drinks per drinking day, WHO risk level, craving all favoured semaglutide. Phosphatidyl ethanol supported self-report. Safety: GI AEs higher (nausea 57% vs 7%). 4 vs 1 discontinued for AEs. No pancreatitis. Caveats: BMI ≥30 only, single centre, no post-trial follow-up. Weight loss correlated with drinking reduction (ρ=-0.40). Moves beyond hypothesis-generating. Replication needed before off-label use.

GLP1's continue to show efficacy in alcohol use disorder treatment- both pre-clinical trials & now blinded placebo controlled

@operationdanish My favorite is when a patient says "But the Dr prescribed x drug" (that they begged for on multiple instances)

You think doctors are making money on those $0.30 SSRIs? I love when tech people think they just know everything. SSRIs are popular because patients are asking for them… because our mental health epidemic is out of control… because tech and social media has made life worse for people. Follow the money back to yourself.

@TheLege2 @rationalaussie Most "Boomers" feel they earned it by enduring the old chest nut of "17% interest rates" & cannot possibly understand the struggles of today's renters / mortgage holders.

@rationalaussie The problem with 'blaming Boomers' is that most Boomers don't know *why* they're doing so well. They just see the prices of their homes and stock portfolios going UP. They don't know why ...

The seeds of the next revolution were sewn when the boomers decided everyone else should socialise their entire lives yet get nothing in return. I really do not think people are prepared for what a future where 'no one cares' anymore looks like. It's not just the poor people that won't care either - it's the smartest, most highly educated people - who correctly conclude there is no winning path in the current system and so would rather tear it to the ground. If people have nothing left to lose, the results really are quite predictable. You really can't claim to be a civilisation that cares for the future when you have a gerontocracy running the place and every single social metric year after year gets worse, but stonks only go up and tech bros only get richer - their reward for automating everyone out of existence? Like has the penny dropped for people yet where this inevitably leads? It's insane how stupid this all is. Everyone is corrupted by a system that is itself deeply corrupted.

Relatively safe pharmacokinetics, too.

Coffee- the stimulant that keeps on giving. Black coffee also has evidence of being beneficial in fatty liver disease

EliLilly has refused to list Mounjaro on PBS,despite PBAC support for t2DM. EliLilly says price offered is unfair? India list price~$40, Au $279-$689, & USA $1,079.77 (US$) month. For a drug that can be produced for $1/vial, & research finding profitability@low cost to cover R&D

11 oil trades, with 11 wins. Perfect timing, every time. BBC validates it. White House denies it. The world is a casino where the house always wins.

One of our most accesible / socially acceptable *rugs happens to be associated with some of the highest rates of morbidity / mortality

Surprising new findings about coffee: you are drinking coffee for the gut bugs that run your brain. > coffee affects the gut which then affects your brain > it's the coffee bean, not the caffeine, doing most of the work > polyphenols feed gut microbes, microbes send chemical messages, brain responds > both coffees lowered inflammation, caffeine drove it further down (IL6, IL10) > decaf raised systemic inflammation markers (hs-CRP, TNF-alpha) > decaf uniquely fed the protective gut microbes > caffeine blocked those gains by pushing food through too fast for the Clostridia bacteria to finish their work > at baseline, coffee drinkers sat in the bottom 25 to 30 percent for protective gut metabolites compared to non-drinkers > coffee lifted mood, cut depression and stress > caffeine specifically lowered anxiety. > the stress hormone story people tell about coffee does not hold up, cortisol did not budge Study details: 62 people, 14-day coffee washout, then 21 days randomized double-blind to caffeinated or decaf. They measured gut bacteria, stool and urine chemistry, cognition, mood, blood inflammation, and cortisol. What to do Caffeinated in the morning for focus and lower anxiety. Decaf in the evening for memory and gut. One cup 6 hours before bed still acts like half a cup at bedtime. Less is better than more either way. The takeaway You are drinking coffee for the bugs that run your brain.