Episodios

  • Ketamine and Sickle Cell Disease - Timing is Everything

    Ketamine and Sickle Cell Disease - Timing is Everything
    Dec 12 2025
    Sickle Cell Disease (SCD) pain crises are the leading cause of hospitalization for affected children, causing excruciating vaso-occlusive episodes where misshapen blood cells block oxygen flow to tissues. For decades, the standard treatment has been high-dose opioids, but this often leads to tolerance, inadequate relief, and the dangerous paradox of opioid-induced hyperalgesia—where the treatment actually makes the nervous system more sensitive to pain. In this episode, we analyze a massive cross-sectional study from 44 U.S. children’s hospitals involving over 74,000 admissions. The study asks a critical question: Can ketamine, an NMDA receptor antagonist that "turns down the volume" on central sensitization, break the cycle of pain where opioids fail? The findings reveal a slow but steady rise in ketamine use (doubling from 2.3% in 2016 to 5.7% in 2023), mostly reserved for older children with severe disease markers like chronic pain or hydroxyurea use. But the most stunning insight is about timing. The study found that when ketamine was administered early (within the first 3 days of admission), it cut the median hospital Length of Stay (LOS) in half—from 12 days to just 6 days—and drastically reduced the days patients needed IV opioids. Despite these compelling results, huge gaps in care remain, with some hospitals using ketamine in 20% of cases and others in 0%. We discuss the institutional barriers, stigma, and red tape that prevent clinicians from using this powerful tool when it matters most: early in the crisis. Reference: Jenkins, A. M., Hendry, E., Power-Hays, A., Valentino, M., Hall, M., Kyler, K. E., Antoon, J. W., Tang Girdwood, S., Goldman, J. L., Morel, A. N., Savage, T. J., Orth, L. E., & Archer, N. M. (2025). Increasing ketamine administration in children's hospitals for youth with sickle cell disease. Blood Advances. https://doi.org/10.1182/bloodadvances.2025016826
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    10 m
  • Will Ketamine Work for Me?

    Will Ketamine Work for Me?
    Dec 5 2025
    "Will this actually work for me?" It is the most critical question patients ask before investing time, money, and hope into ketamine therapy. In this episode, we analyze a massive body of research—including a systematic review of 112 studies and a real-world analysis of 77 patients —to find actionable predictors of success. The results are reassuringly broad: factors like age, sex, depression severity, trauma history, and even the intensity of dissociation do not predict whether ketamine will work. However, the data reveals two powerful signals that every patient should know: The "Line in the Sand": The strongest negative predictor is pharmacological resistance. Patients who have failed more than six previous antidepressant trials were significantly less likely to respond to ketamine. The "Perfect" Positive Signal: Researchers identified an early marker of success after just the second infusion. A tiny symptom reduction of just 4.1% on the PHQ-9 scale carried a Positive Predictive Value of 1.0—meaning 100% of patients who hit this mark went on to achieve a clinical response. Crucially, we explain why early non-improvement does not mean failure, as nearly half of patients who showed zero improvement after dose two still achieved a response by the end of treatment. Join us to learn why ketamine might need to be considered earlier in the treatment timeline, before pharmacological resistance sets in. Reference: Syed, O. A. (2025). Predictors of the antidepressant effects of ketamine and psychedelic substances [Master's thesis, University of Toronto]. TSpace Repository.
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    10 m
  • Ketamine, Sleep, and Oral Bacteria – A Microbial Mystery

    Ketamine, Sleep, and Oral Bacteria – A Microbial Mystery
    Nov 30 2025
    Surgery is a trauma that wrecks sleep, and for vulnerable patients, Post-Operative Sleep Disturbance (PSD) is a serious complication linked to delirium, increased pain, and slowed recovery. In this episode, we dive into a fascinating study that connects three seemingly unrelated dots: ketamine, sleep, and the oral microbiome. Researchers treated 130 high-risk surgical patients with a continuous low-dose infusion of esketamine. The clinical results were striking: the rate of PSD dropped from 65% in the control group to just 43% in the esketamine group. Patients reported significantly better sleep quality and required far fewer opioids like hydromorphone. But the real surprise was found in their saliva. The study revealed that esketamine treatment actively reshaped the oral microbial community—boosting beneficial bacteria like Streptococcus while suppressing groups like Bacteroidota that were linked to poor sleep. Why would an IV anesthetic change mouth bacteria? We explore the leading theories: Systemic Anti-Inflammation: Surgery floods the body with pro-inflammatory cytokines (a "systemic fire"). Ketamine’s powerful anti-inflammatory properties may calm this environment, making the host less hospitable to stress-related microbes. The Gut-Oral Axis: Ketamine may influence the gut microbiome, with effects rippling up to the mouth to stabilize the body's entire ecosystem. This research challenges us to rethink how psychiatric drugs work—not just by hitting receptors in the brain, but by restoring ecological balance to the nerves, immune system, and the trillions of microbes that live within us. Reference: Li, X.-Y., Qiu, D., Du, N., Hashimoto, K., Wang, X.-M., & Yang, J.-J. (2025). Esketamine prevents postoperative sleep disturbance in patients with preoperative sleep disorders: A role for oral microbiota. Translational Psychiatry, 15(1), 501. https://doi.org/10.1038/s41398-025-03705-9
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    8 m
  • Ketamine for Catatonia – Unlocking the Frozen Brain

    Ketamine for Catatonia – Unlocking the Frozen Brain
    Nov 21 2025
    Catatonia is often misunderstood as simple immobility, but it is a terrifying, life-threatening syndrome of stupor, mutism, and extreme negativism—a state where the brain is essentially "frozen." For decades, the standard protocol has been to step on the "brake pedal" using GABA-ergic drugs like lorazepam, followed by Electroconvulsive Therapy (ECT) if medication fails. But what happens when the brakes don't work, and ECT is medically unsafe or unavailable? This episode analyzes a new systematic review of 10 unique case reports that suggests NMDA receptor antagonists like ketamine and esketamine could be the "skeleton key" for these desperate scenarios. We explore the neurochemistry of switching from the failed inhibitory (GABA) pathway to directly targeting the excitatory (Glutamate) system. The theory? Refractory catatonia may be driven by a massive glutamate hypo-function—the brain's engine isn't firing—and ketamine triggers the necessary surge to reset the circuit. The clinical results discussed are striking: 100% of the patients in the review showed symptom improvement, often within hours to days. We also debunk the common fear that ketamine might destabilize these fragile patients by triggering mania or psychosis; the review found these risks were not supported by the data. Finally, we highlight the practical game-changer of intranasal esketamine, which allows clinicians to bypass the resistance often seen in mute, withdrawn patients who cannot swallow pills. Reference: van der Meer, P. B., Verboeket, S., Slooter, A. J. C., Schoones, J. W., van Noorden, M. S., Somers, M., Batalla, A., & Dols, A. (2025). Treatment with (es)ketamine in catatonia: A systematic review of case reports. The Journal of Clinical Psychiatry, 86(4), Article 25br15940. https://doi.org/10.4088/JCP.25br15940
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    15 m
  • Ketamine for Complex Regional Pain Syndrome (CRPS)

    Ketamine for Complex Regional Pain Syndrome (CRPS)
    Nov 13 2025
    We move beyond depression and anesthesia to examine ketamine's role in fighting one of the most severe types of chronic pain imaginable: Complex Regional Pain Syndrome (CRPS). This condition is marked by wildly disproportionate and persistent pain , exemplified by the case of a 15-year-old athlete whose simple hand fracture healed, but whose nervous system got stuck in a pathological pain loop. The core problem in CRPS is central sensitization—the brain and spinal cord jamming the "volume knob" for pain on maximum, where a light touch (allodynia) is interpreted as excruciating. Traditional treatments fail because the problem is upstream, residing in the central nervous system (CNS). Specialists employed a clever, multimodal strategy to finally break this refractory pain cycle: Gabapentin: To calm general static in the nervous system. Continuous Nerve Block: A regional anesthetic to temporarily silence all incoming peripheral pain signals from the arm. Continuous Ketamine Infusion: The NMDA receptor antagonist was the core component, performing a "software reboot" on the CNS. Ketamine acts as a master switch, physically blocking the NMDA receptor that powers the central sensitization system, thereby interrupting the vicious wind-up cycle. The results were dramatic: pain, which was agonizing, dropped from 7/10 to 2/10 within 24 hours, resolving completely in 48 hours. Allodynia resolved, enabling the essential physiotherapy needed for long-term recovery. This case report is a powerful demonstration of ketamine's versatility, showing it can act not just as a painkiller, but as a system reset for neurological conditions rooted in faulty learning. Reference: Medikondu, H., Davit, A., & Visoiu, M. (2025). Effective Adolescent Hand CRPS Type 1 Treatment Using Ketamine, Gabapentin, and Supraclavicular Nerve Block Catheter. Preprints.org. https://doi.org/10.20944/preprints202511.0755.v1
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    9 m
  • Ketamine and Longevity

    Ketamine and Longevity
    Nov 6 2025
    Chronic mental illnesses like severe MDD (major depressive disorder) and PTSD are alarms, not just for the mind, but for the body. This episode explores the fact that ongoing trauma and depression accelerate biological aging, leading to reduced health span and higher risks for chronic diseases. But can rapid, effective psychiatric treatment actually reverse this damage? We dive into a compelling pilot study that gave a series of six sub-anesthetic ketamine infusions to 20 participants with treatment-resistant depression or PTSD. The researchers used second-generation epigenetic clocks to measure biological age—the actual cellular wear and tear, separate from chronological age. The most advanced clock used, OMICs-AGE, integrates DNA methylation with surrogates for over 40 proteins, metabolites, and clinical markers across eight physiological systems, showing the strongest link to mortality risk. The findings are potentially groundbreaking: Age Reversal: The study found a clear, statistically significant reduction in epigenetic age across several markers after treatment. Critically, the signal captured by OMICs-AGE held up under stringent statistical correction, suggesting a genuine biological age deceleration. The Mechanism: This reversal is linked to specific anti-aging pathways. Ketamine treatment led to a significant reduction in CD4 T memory cells, which are markers for systemic inflammation and aging (immunosenescence). Further analysis revealed shifts in metabolic and neuroimmune markers clustered around circadian sleep regulation and T-cell differentiation. While this was a small pilot study without a non-treatment control group , the robustness of the OMICs-AGE signal suggests a profound implication: the ultimate longevity treatment may lie not in anti-aging creams, but in aggressively treating the mental illness that accelerates the biological clock in the first place. Mental health truly is longevity health. Reference:
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    15 m
  • A Flawed Ketamine Trial?

    A Flawed Ketamine Trial?
    Oct 30 2025
    The KARMA-Dep2 trial delivered a shocking headline: up to eight serial ketamine infusions were no better than the midazolam placebo for hospitalized adults with moderate to severe depression. In an era of intense hope for ketamine's rapid antidepressant effects, this result demands a closer look. This episode critically dissects why this large, pragmatic trial may have failed to show a significant difference, focusing on a central challenge in ketamine research: blinding. The Active Placebo Problem: The trial used midazolam as an active placebo to mimic the transient side effects (like sedation and disorientation) of ketamine. However, previous meta-analyses (Wilkinson et al., 2019) show that midazolam itself produces a substantial placebo/expectancy effect (around an 18% response rate), effectively setting a high floor that makes the pharmacological benefit of ketamine harder to detect. The Unblinding Issue: We contrast the KARMA-Dep2 outcome with the Dwyer et al. (2021) adolescent trial, where ketamine was significantly better than midazolam. Crucially, the adolescent study revealed a massive confound: 10 out of 10 patients on ketamine correctly guessed their treatment, illustrating the "functional unblinding" that allows expectation to heavily influence results. The Measurement Challenge: We discuss the inherent difficulty of using scales designed for slow-acting drugs (like MADRS and HAMD) to measure ketamine's rapid antidepressant effects, leading to measurement workarounds like carrying over scores for symptoms like sleep and appetite. The core question remains: Does midazolam give a truly realistic estimate of ketamine's effect, or does chasing the "perfect blind" with an active placebo simply obscure the real-world value of a drug whose unique, powerful experience is inseparable from its clinical benefit? Resources: Wilkinson, S. T., Farmer, C., Ballard, E. D., Mathew, S. J., Grunebaum, M. F., Murrough, J. W., Sos, P., Wang, G., Gueorguieva, R., & Zarate, C. A., Jr. (2019). Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant. Neuropsychopharmacology, 44, 1233–1238. https://doi.org/10.1038/s41386-019-0317-8 Dwyer, J. B., Landeros-Weisenberger, A., Johnson, J. A., Londono Tobon, A., Flores, J. M., Nasir, M., Couloures, K., Sanacora, G., & Bloch, M. H. (2021). Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial. American Journal of Psychiatry, 178(4), 352–362. https://doi.org/10.1176/appi.ajp.2020.20010018 Jelovac, A., McCaffrey, C., Terao, M., Shanahan, E., Whooley, E., McDonagh, K., McDonogh, S., Loughran, O., Shackleton, E., Igoe, A., Thompson, S., Mohamed, E., Nguyen, D., O'Neill, C., Walsh, C., & McLoughlin, D. M. (2025). Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression: The KARMA-Dep 2 Randomized Clinical Trial. JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2025.3019 
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    Menos de 1 minuto
  • Ketamine and Liver Damage?

    Ketamine and Liver Damage?
    Oct 23 2025
    For years, the most recognized physical risk of chronic ketamine abuse has been bladder damage, but a new clinical puzzle is emerging: severe injury to the liver and bile ducts, known as Ketamine-induced Sclerosing Cholangitis (K-SC). This episode dives into a recent case series detailing patients—including older and female European users—broadening the picture of who is at risk. Sclerosing cholangitis is a progressive condition where chronic inflammation leads to severe scarring and narrowing of the bile ducts. This obstruction causes bile backup (cholestasis), which, if unchecked, can result in irreversible cirrhosis—often making a liver transplant the only option. We explain why laboratory markers like GGT and ALP are critical red flags for this damage. How does this anesthetic target the liver's plumbing? The leading hypothesis suggests chronic, high-dose exposure over time causes sustained spasms due to ketamine's effect on NMDA receptors located in the bile duct smooth muscle. Crucially, the severity of this liver damage often tracks directly with the severity of a patient's urinary symptoms, suggesting a systemic toxic effect on similar smooth muscle tissues in both the bladder and the biliary system. Using diagnostic criteria, physicians confirmed K-SC by ruling out other look-alike conditions (like PSC, which is tied to IBD). The strongest evidence linking the drug to the severe damage was the dramatic clinical improvement in lab results immediately after patients ceased ketamine use. The main takeaway for anyone concerned is non-negotiable: the absolute first line of defense is immediate and permanent cessation of all ketamine use. Management requires a comprehensive multidisciplinary team—gastroenterologists, urologists, and addiction specialists—to manage the devastating progression and provide essential addiction support. This exploration underscores a tragic potential consequence of long-term abuse and the urgent need for more longitudinal research. Source Research Paper: Vanrusselt, A., Nijs, J., Van den Bergh, L., Schoofs, N., Smets, S., Strybol, D., & Rappaport, A. (2025). Ketamine-induced sclerosing cholangitis: a case series. Acta Gastro-Enterologica Belgica, 88(3), 271–276. https://doi.org/10.51821/88.3.13914
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    13 m