Scott Alexander examines the surprisingly broad effects of GLP-1 drugs like Ozempic, exploring their mechanisms and speculating on why they seem to impact so many different conditions. Longer summary

Scott Alexander explores the wide-ranging effects of GLP-1 receptor agonist medications like Ozempic, which are approved for diabetes and obesity but show promise for many other conditions. He delves into the mechanisms behind their effects on diabetes, weight loss, and addiction, speculating on why these drugs seem to have such broad impacts. The post discusses how GLP-1 drugs work in the brain to reduce hunger and dampen reward systems, potentially explaining their effects on addiction. Scott also touches on their anti-inflammatory properties and potential benefits for neurodegenerative diseases, while cautioning that some reported effects may not replicate. Shorter summary

Scott explores GABA-A receptor subunits, their effects, and how various drugs interact with them, discussing potential for more selective drug development. Longer summary

This post explores GABA-A receptor subunits and their role in psychiatric drugs and supplements. It explains the structure of GABA-A receptors, focusing on the alpha subunits and their associated effects. The post discusses how different drugs like benzodiazepines and zolpidem (Ambien) interact with these subunits, and mentions attempts to create more selective drugs. It also touches on the role of GABA receptors in alcohol's effects and the classification of Z-drugs. The author includes personal experiences with supplements claiming to have selective GABA modulation. Shorter summary

Scott Alexander investigates the optimal dosage of Lexapro, comparing it to other antidepressants and exploring the reasons behind its effectiveness at lower doses. Longer summary

Scott Alexander explores the question of the right dose for Lexapro (escitalopram), an antidepressant. He examines official recommendations, compares Lexapro to other SSRIs, and investigates why Lexapro might be effective at lower doses. The post delves into studies on antidepressant dosing, the unique properties of Lexapro, and the potential benefits and risks of higher doses. Scott concludes that while there's no strong evidence for high doses of any antidepressant being more effective, prescribing higher doses of Lexapro might be as safe as other SSRIs and potentially more beneficial in some cases. Shorter summary

Scott Alexander explores the history and mechanism of DNP, a dangerous but effective weight-loss drug, and discusses recent developments in safer mitochondrial uncoupling agents. Longer summary

Scott Alexander discusses 2,4-dinitrophenol (DNP), a controversial and dangerous weight-loss drug that works by uncoupling mitochondria. He traces its history from the 1930s to modern times, explaining its effectiveness and severe side effects. The post then explores recent developments in mitochondrial uncoupling research, including potential safer alternatives and therapeutic applications beyond weight loss. Shorter summary

Scott Alexander critically examines a new theory on antidepressant mechanisms, expressing skepticism while acknowledging its potential significance if proven true. Longer summary

Scott Alexander reviews a recent study proposing a new theory for how antidepressants work, which suggests they bind directly to TrkB receptors rather than acting through serotonin. He explains the study's findings and their potential implications, but expresses skepticism about the theory. Scott outlines several reasons why he finds the new theory unconvincing, including existing evidence supporting the serotonin hypothesis, issues with the study's claims about drug accumulation, and expert opinions on the difficulties of TrkB research. He concludes by stating he will stick with the conventional theory for now, while remaining open to future developments. Shorter summary

Scott Alexander examines a theory proposing that depression, anxiety, and trauma are characterized by low precision of sensory evidence, leading to overreliance on negative priors. Longer summary

Scott Alexander discusses a paper by Van der Bergh et al. that proposes a unified theory of negative emotionality, including depression, anxiety, and trauma. The theory suggests that these conditions are characterized by a processing style that assigns unusually low precision to sensory evidence, leading to an overreliance on negative priors. Scott explores the implications of this theory, including its support for various psychotherapies, somatic therapies, and meditation. He also discusses potential pharmacological interventions and how this model ties together various concepts in psychiatry and predictive processing. Shorter summary

Scott Alexander examines the history, chemistry, and efficacy of various amphetamine-based ADHD medications, comparing their strengths and weaknesses. Longer summary

Scott Alexander explores the history and differences between various amphetamine-based ADHD medications. He traces the origins of Adderall to a 1950s diet pill, then compares it to other drugs like Dexedrine, Vyvanse, Evekeo, and Desoxyn (methamphetamine). The post discusses the chemical differences, patient preferences, and effectiveness of these medications, noting that pure d-amphetamine (Dexedrine) seems generally superior to the Adderall mixture. Scott also touches on the controversy surrounding methamphetamine use in ADHD treatment, explaining that the main differences between therapeutic use and abuse are dosage and administration method rather than inherent properties of the drug. 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 explores Hallucinogen Persisting Perception Disorder (HPPD) and other conditions where drugs cause permanent effects, discussing potential mechanisms and their implications. Longer summary

Scott Alexander discusses Hallucinogen Persisting Perception Disorder (HPPD), a condition where some people experience permanent hallucinatory effects after using psychedelic drugs, particularly LSD. He explores the prevalence, potential mechanisms, and implications of this disorder. The post compares HPPD to other conditions with persistent effects like tardive dyskinesia, and examines various theories about how drugs could cause permanent changes in the brain. Scott considers two main hypotheses: the killing-off of specific neurons, and the idea of the brain as a chaotic system settling into new attractor states. He expresses a preference for the neuron death theory as it seems more understandable and less scary, but acknowledges the complexity and uncertainty surrounding these issues. 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 Alexander explores the complexities and inconsistencies of drug tolerance in psychiatry, highlighting how different drugs can produce varying tolerance effects across individuals. Longer summary

Scott Alexander discusses the complex and often unpredictable nature of drug tolerance in psychiatry. He explores various examples of how different drugs can lead to tolerance, no tolerance, or even reverse tolerance (increased sensitivity) in different individuals. The post highlights the inconsistencies in how tolerance develops across various drugs and patients, and how this impacts psychiatric treatment. Scott expresses frustration with the lack of attention given to tolerance in psychiatric literature and the difficulty in predicting or explaining tolerance patterns. He also touches on how this unpredictability relates to addiction, the potential for missed opportunities in drug development, and the need for better understanding of tolerance mechanisms. Shorter summary

Scott Alexander analyzes online drug ratings, finding patients prefer older antidepressants while doctors prefer newer ones, and explores potential explanations for this paradox. Longer summary

Scott Alexander analyzes patient ratings of antidepressants from online databases, finding that older drugs like MAOIs are rated higher than newer ones. He then compares this to doctor ratings, discovering a negative correlation between patient and doctor preferences. The post explores possible explanations for these paradoxical results, including confounding factors and the hypothesis that newer antidepressants may actually be less effective. Scott extends the analysis to other drug classes, finding the negative doctor-patient correlation holds broadly, while the preference for older drugs is specific to psychiatric medications. Shorter summary