A detailed insider look at Phase I clinical drug trials, revealing how the system's structure encourages participants to routinely lie about their medical history and symptoms to continue participating. Longer summary

This review explores Phase I clinical pharmaceutical trials from a participant's perspective, detailing the process, the people involved, and systemic issues. The author explains how participants are recruited, screened, and monitored during trials, then describes the peculiar demographics of regular trial participants. A key focus is how the system's incentives encourage dishonesty: participants routinely lie about medical history and symptoms because being truthful often leads to disqualification from future trials. The author concludes that while this systemic dishonesty probably doesn't catastrophically compromise drug safety, it does make the research pipeline less effective than it could be. Shorter summary

A guest post defending the amyloid hypothesis of Alzheimer's disease, explaining why amyloid is likely the root cause despite recent criticism and discussing why early treatments have only been partially effective. Longer summary

David Schneider-Joseph presents a detailed defense of the amyloid hypothesis of Alzheimer's disease, which states that the disease is caused by accumulation of amyloid-β peptide. He explains the ATN model (amyloid → tau → neurodegeneration) and provides extensive evidence from genetics, clinical studies, and animal models. The post addresses various criticisms of the hypothesis, including the recent research fraud controversy and apparent failures of early treatments. The author explains why current treatments have only achieved about 30% efficacy and predicts that future treatments targeting amyloid earlier and more effectively could achieve much better results. Shorter summary

Scott Alexander and 1DaySooner outline potential positive health policy initiatives that could emerge under three key Trump administration health appointees: Jim O'Neill, Marty Makary, and Jay Bhattacharya. Longer summary

This post discusses potential health policy proposals under a hypothetical second Trump administration, focusing on three key appointees and their possible initiatives. The piece examines Jim O'Neill as Deputy Secretary of HHS, highlighting his potential work on organ donation compensation and longevity research; Marty Makary as FDA Commissioner, discussing FDA transparency and regulatory improvements; and Jay Bhattacharya as NIH Director, exploring research funding reforms and challenge trials. Written in collaboration with 1DaySooner, the post specifically focuses on optimistic scenarios that could emerge from these appointments. Shorter summary

Scott Alexander examines Zulresso and Zuranolone, two neurosteroid drugs for postpartum depression, discussing their efficacy, challenges, and potential future applications. Longer summary

Scott Alexander discusses Zulresso (allopregnanolone) and Zuranolone, two related drugs for treating postpartum depression. He explains their mechanisms, efficacy, and the challenges in their development and usage. The post covers the history of allopregnanolone research, its connection to GABA and hormones, clinical trials, and potential future applications. Scott also discusses the high cost of Zulresso, its limited availability, and the mixed results of Zuranolone in treating regular depression and anxiety. The post ends with predictions about the future of these drugs and related research. Shorter summary

Scott Alexander argues that doctors should prescribe fluvoxamine for COVID-19 despite FDA inaction, urging them to overcome discomfort with off-label use when evidence supports it. Longer summary

Scott Alexander discusses the use of fluvoxamine (Luvox) as a potential treatment for COVID-19. He argues that despite strong evidence from clinical trials showing its effectiveness, many doctors are hesitant to prescribe it due to it being off-label use. The FDA has not added COVID-19 to the drug's label, citing bureaucratic issues. Scott criticizes this inaction and suggests that doctors should be willing to prescribe off-label when evidence supports it, even if it feels uncomfortable. He relates personal experiences of hesitating to prescribe off-label medications due to social pressure and encourages doctors to critically examine their reasons for not prescribing fluvoxamine for COVID-19. Shorter summary

Scott summarizes and responds to comments on his previous article about FDA approval of Paxlovid, acknowledging some valid points while maintaining his criticism of the approval process. Longer summary

This post summarizes comments on Scott's previous article about FDA approval of Paxlovid. It covers manufacturing challenges, FDA approval processes, production capacity, ongoing studies, and ethical considerations. Scott acknowledges some valid points raised by commenters about reasons for FDA delays, but maintains his criticism of the approval process, suggesting a need for different levels of approval and questioning the current drug approval system. Shorter summary

Scott Alexander reviews comments on his posts about aducanumab and the FDA, acknowledging some mistakes while defending his overall critique of FDA conservatism. Longer summary

Scott Alexander reviews comments on his recent posts about aducanumab and the FDA. He acknowledges some mistakes in his original post, but defends his overall critique of the FDA as overly conservative. The comments cover various aspects of drug approval, including the aducanumab controversy, surrogate endpoints, the FDA's impact on small biotech companies, and comparisons to other regulatory systems. Scott reflects on how to improve his fact-checking process while still writing passionate pieces. Shorter summary

Scott Alexander examines the development and effectiveness of vilazodone and vortioxetine, two antidepressants designed to work faster and better than SSRIs, but which ultimately failed to live up to expectations. Longer summary

Scott Alexander discusses the development and effectiveness of two antidepressants, vilazodone and vortioxetine, which were designed to combine SSRI effects with 5-HT1A partial agonism. He explains the theoretical basis for their development, involving the role of presynaptic 5-HT1A autoreceptors in delaying SSRI effectiveness. The post then evaluates the clinical performance of these drugs, finding that despite their innovative design, they don't significantly outperform older antidepressants in efficacy, onset speed, or side effect profile. Scott expresses confusion about the theoretical underpinnings of these drugs and why pharmaceutical companies invested so heavily in their development. Shorter summary

Scott Alexander analyzes the PANDA Study, a large real-world antidepressant trial, discussing its methodology, results, and implications for understanding antidepressant efficacy. Longer summary

This post discusses the PANDA (Prescribing ANtiDepressants Appropriately) Study, the largest non-pharma antidepressant trial ever conducted. The study aimed to measure the real-world efficacy of antidepressants, specifically sertraline, in a naturalistic setting. Scott Alexander analyzes the results, which show small to low-medium effect sizes for various depression and anxiety measures. He notes that while the effects are modest, they are not clinically insignificant. The study found that patient-reported improvement had a higher effect size than researcher-measured tests, potentially indicating a disconnect between clinical measures and patient experiences. Scott discusses the implications of these findings for antidepressant efficacy and suggests that targeted treatment approaches might yield better results. Shorter summary

Scott Alexander critiques the FDA approval of esketamine for depression, discussing issues with drug development, efficacy, cost, and administration requirements. Longer summary

This post discusses the FDA's approval of esketamine for treatment-resistant depression, highlighting the issues with the pharmaceutical industry's approach to drug development and approval. Scott Alexander explains how companies often make minor changes to existing chemicals to patent them, as in the case of esketamine (a left-handed version of ketamine). He critiques the high cost of esketamine compared to regular ketamine and the FDA's stringent requirements for its administration. The post also questions the efficacy of esketamine based on clinical trials and discusses the inconvenience of the approved delivery method. Scott expresses disappointment that this approval may set a precedent for future psychedelic medicines, making them equally inconvenient and bureaucratic to access. Shorter summary

Scott Alexander introduces an 'Anxiety Sampler Kit' for testing various anxiety supplements, aiming to personalize treatment and gather data through self-experimentation. Longer summary

Scott Alexander introduces an experimental 'Anxiety Sampler Kit' designed to test the effectiveness of various supplements for treating anxiety. The kit contains 21 boxes with six different supplements and placebos, arranged randomly. Users try a box when feeling anxious, rate their response, and after completing all boxes, determine which supplement worked best for them. This approach aims to personalize treatment and gather data for a small placebo-controlled trial. Scott discusses the rationale behind personalized medicine and the challenges in predicting individual treatment responses. He invites Bay Area residents to participate in this self-experimentation project, with the condition that they share their results. Shorter summary

Scott Alexander examines the rise, fall, and alleged resurrection of the antidepressant NSI-189, expressing skepticism about its efficacy and the broader challenges in developing new antidepressants. Longer summary

Scott Alexander discusses the disappointing results of NSI-189, a promising new antidepressant, in FDA trials. He explains how the drug initially failed to outperform placebo on the primary endpoint, leading to a stock crash for Neuralstem. However, the company later released positive secondary endpoint results, causing their stock to rise again. Scott expresses skepticism about these new results, suggesting they may be due to statistical manipulation rather than true efficacy. He reflects on the challenges of developing new antidepressants and the tendency to get overly excited about new drugs, ending with a sardonic hope for another new antidepressant, SAGE-217. Shorter summary

Scott Alexander argues that the 33% rate of post-marketing safety events for FDA-approved drugs is not necessarily concerning and explains why post-marketing surveillance is a normal part of drug safety monitoring. Longer summary

Scott Alexander discusses a study showing that 33% of FDA-approved drugs in the past decade have faced post-marketing safety events. He argues that this doesn't necessarily mean the FDA is too lax, explaining that post-marketing surveillance is a normal and necessary part of drug safety monitoring. He points out that only 1.3% of drugs were actually withdrawn from the market, which he considers a good success rate. Scott explains why it's impossible to catch all potential side effects in pre-approval studies and gives examples of safety communications that range from important to seemingly trivial. He concludes that the 33% figure alone is meaningless without a broader cost-benefit analysis of FDA approval standards. Shorter summary

Scott analyzes various criticisms of antidepressants, concluding they have modest but real benefits over placebo, with important considerations about side effects and efficacy. Longer summary

This post examines various criticisms of SSRIs and antidepressants, addressing claims about their efficacy, side effects, and comparisons to placebo and psychotherapy. Scott analyzes studies on antidepressant effectiveness, discussing issues like publication bias, effect sizes, and the meaning of 'clinical significance'. He explores side effects, particularly sexual dysfunction, weight gain, and emotional blunting. The post concludes that while antidepressants are not miracle drugs, they do have a modest but statistically significant benefit over placebo and can be a reasonable option for many people with depression, especially if they understand and prepare for potential side effects. Shorter summary

A short story about a genie granting a wish for the cure to cancer, with a twist highlighting the practical challenges of drug development and approval. Longer summary

This post is a short fictional story about a genie and a wish. The narrator frees a genie from a lamp and is granted one question. They ask for the cure for cancer, and the genie provides a specific answer: a compound called oxymercuriphine from the venom of the two-toed toad of Toronto. The twist comes when the genie, while technically fulfilling the wish, points out the practical difficulties of bringing such a cure to market due to the expensive and time-consuming FDA approval process. Shorter summary