Clinicians measure success in symptom scores and receptor occupancy, but for patients with Treatment-Resistant Depression (TRD), success is defined by something far more personal: the return of connection, clarity, and “life.” In this episode, we amplify the “Patient’s Voice” through a comprehensive synthesis of qualitative studies by Walasek and colleagues.

We trace the emotional arc of treatment, starting with the profound ambivalence of patients who see ketamine as a “last resort”—terrified it will be just another failure in a long line of disappointments. We then step inside the acute experience itself, often described as a “rollercoaster” where euphoria and panic can flip on a dime, making the safety of the setting and the empathy of the staff critical to preventing trauma.

The discussion challenges the medical model’s obsession with dissociation as a measurable “active ingredient,” revealing that patients value the meaning they make of the experience—the moments of insight and emotional release—far more than the intensity of the “trip” itself. Finally, we expose the hidden barriers to care: the crushing financial burden, the stigma of using a “party drug,” and the finding that patients often attribute up to 50% of their therapeutic outcome not to the molecule, but to the kindness and support of the clinical staff.

Reference:

Walaszek, M., Cubała, W. J., & Kachlik, Z. (2025). Patients’ voices on ketamine for treatment-resistant depression: A narrative review of qualitative perspectives. Journal of Clinical Medicine.

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For decades, the “trip” caused by ketamine—sensory detachment, time warping, and out-of-body experiences—was seen as a nuisance, a “bug” to be tolerated during anesthesia. But a groundbreaking 2025 review paper by Berra and colleagues asks a provocative question: What if dissociation is actually the point?

In this episode, we dive into the “Science of Dissociation,” exploring the spectrum from simple “checking out” (daydreaming) to profound depersonalization and derealization. We analyze the “switch” in the brain—how ketamine blocks NMDA receptors on inhibitory interneurons, unleashing a glutamate burst that disrupts the Default Mode Network (DMN). This disruption forces the brain into a “chaotic” state of higher entropy, breaking rigid, depressive thought loops and allowing the mind to form new, healthier connections.

We also look to the future of “non-hallucinogenic” alternatives like hydroxynorketamine (HNK), which promote neuroplasticity without the trip. This raises a fundamental philosophical and clinical question: Is the conscious experience of an altered state the “price of admission” for healing, or can we bypass the mind to fix the brain?

Reference:

Bera, K., Looger, L. L., Proekt, A., & Cichon, J. (2025). Cortical mechanisms contributing to ketamine-induced dissociation. The Neuroscientist, 1–17. https://doi.org/10.1177/10738584251403946

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For decades, ketamine has been viewed primarily through two lenses: a safe anesthetic or a rapid-acting antidepressant “reset button.” But a new paper by Sophie Holland argues we may be missing half the picture. This episode challenges the binary view of ketamine by exploring two distinct therapeutic pathways defined essentially by dose: the Psychedelic and the Psycholytic.

The discussion also tackles the debate over ketamine’s classification—is it truly a psychedelic? While chemically distinct from “classic” psychedelics like psilocybin, its ability to induce neuroplasticity (acting as a psychoplastogen) and non-ordinary states of consciousness places it firmly in the psychedelic therapeutic spectrum.

Finally, we look at the physical realities. With chronic high-dose use linked to ulcerative cystitis, does the low-dose psycholytic approach offer a safer, more sustainable model for long-term relational work?. We also touch on the frontier of “betterment of the well,” exploring how low-dose protocols might enhance creativity, teamwork, and problem-solving in healthy individuals.

Reference:

Holland, S. (2025). Ketamine reimagined: Distinguishing psychedelic and psycholytic modalities for next-generation therapies. Silva Wellness. DOI: 10.22541/au.176538434.48451693/v1

The post Ketamine Reimagined – Reset Button or Relational Tool? appeared first on Talking Ketamine Podcast.

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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“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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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:

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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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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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:

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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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:

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:

Dawson, K. L., Carangan, A. M. J. M., Klunder, J., Carreras-Gallo, N., Sehgal, R., Megilligan, S., Askins, B. C., Mendez, T. L., Smith, R. M., Dawson, M. S., Mallin, M. P., Higgins-Chen, A. T., & Dwaraka, V. B. (2025). Epigenetic aging and DNA methylation biomarker changes following ketamine treatment in patients with MDD and PTSD: a pilot study. Translational Psychiatry, 15(1), 452. https://doi.org/10.1038/s41398-025-03683-y

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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 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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