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The Emerging Crisis in Non-Prescribed Ketamine Use: A Rapid Attenuation of Depression in Face of Abuse and "Chill-out" or Escapism Drug.

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Title: The Emerging Crisis in Non-Prescribed Ketamine Use: A Rapid Attenuation of Depression in Face of Abuse and "Chill-out" or Escapism Drug.
Authors: Lewandrowski, Kai Uwe (AUTHOR), Blum, Kenneth (AUTHOR), Schmidt, Sergio (AUTHOR), Alvim Fiorelli, Rossano Kepler (AUTHOR), Gold, Mark S. (AUTHOR), Mohankumar, Kavya (AUTHOR), Sharafshah, Alireza (AUTHOR), Bagchi, Debasis (AUTHOR), Pinhasov, Albert (AUTHOR), Lorio, Morgan P. (AUTHOR), Modestino, Edward J. (AUTHOR), Madigan, Margaret A. (AUTHOR), Baron, David (AUTHOR), Lewandrowski, Alexander P. L. (AUTHOR), Dennen, Catherine A. (AUTHOR), Thanos, Panayotis K. (AUTHOR), Badgaiyan, Rajendra D. (AUTHOR)
Source: Substance Use & Misuse. 2026, Vol. 61 Issue 9, p1532-1549. 18p.
Subjects: Prevention of mental depression, Substance abuse, Ketamine, Epigenomics, Prefrontal cortex, Neuroplasticity, Treatment effectiveness, Brain diseases, Antidepressants, Suicide prevention, Pharmacogenomics, Serotonin, Mental depression, Drug resistance, Neurotransmitters, Psychiatric drugs, Nonprescription drugs, Pharmacodynamics
Geographic Terms: United States, United Kingdom, Europe
Abstract: Background: Since 2000, rates of suicide and opioid overdose have sharply increased. Approximately one-third of individuals with major depressive disorder (MDD) experience treatment-resistant depression (TRD), highlighting the urgent need for novel therapeutic approaches. Objective: This review synthesizes pivotal preclinical and clinical findings on low-dose ketamine's rapid antidepressant effects and examines proposed mechanisms underlying its therapeutic action. Methods: This is a narrative review of key contributions in the literature addressing ketamine's fast-acting antidepressant properties. Results: Low-dose ketamine rapidly alleviates depressive symptoms, including in refractory depression. Despite multiple hypotheses supported by preliminary data, there is no consensus regarding its definitive mechanism of action. Proposed mechanisms include modulation of dopamine signaling via epigenetic neuroadaptation, interactions with D1/D2 receptor systems, optogenetic activation of D1 pathways, and alterations in D2/D3 receptor availability. Conclusions: Elucidating ketamine's mechanism of action may inform the development of next-generation psychoplastogens that promote neural plasticity in TRD and unipolar MDD. However, ketamine's psychoactive properties and abuse potential, along with concerns regarding misuse and diversion, underscore the need for enhanced clinical oversight and regulatory frameworks. PREAMBLE: A recent editorial in the British Medical Journal (BMJ) highlighted a dramatic rise in non-prescribed ketamine use in the UK, with over 3,600 individuals seeking treatment for ketamine addiction in 2023–2024, an eightfold increase compared to a decade earlier. This trend is not isolated to the UK; misuse has surged across Europe and the United States. It is worth noting that as early as 2015, the BMJ cautioned against overstating ketamine's antidepressant benefits and warned of its methodological flaws and risks of misuse, warnings that appear to have been largely overlooked (Zhang & Ho, 2015). Once confined to occasional recreational use in nightlife settings, ketamine is now frequently self-administered at home, often daily, by individuals attempting to manage symptoms of anxiety, depression, PTSD, or chronic stress without medical oversight. Despite its therapeutic promise at controlled doses, ketamine carries well-established risks. A 2016 publication by one of the present authors outlined these concerns early on. The BMJ editorial affirms ketamine-associated urotoxicity, which can manifest as urinary incontinence, severe bladder pain (commonly referred to as "K-cramps"), and reduced bladder capacity, sometimes necessitating surgical intervention, including bladder removal. The editorial also reported new adverse outcomes from chronic use, including cognitive deficits, affective disturbances (e.g., anxiety, depression, psychosis), gastrointestinal complications, and renal injury. Ceban et al. (CNS Drugs, 2021) reported that while most ketamine- and esketamine-related adverse effects are mild and transient, clinicians should remain vigilant regarding potential long-term toxicity and abuse liability. Ng et al. (Psychopharmacology, 2021) further demonstrated that chronic or high-frequency ketamine exposure may lead to urothelial inflammation and bladder dysfunction, highlighting the importance of monitoring genitourinary symptoms during treatment (Ceban et al., 2021; Ng et al., 2021). Though ketamine-related fatalities remain comparatively low, the numbers are steadily rising. The drug remains accessible and inexpensive, often costing less than cocaine. DEA data show a sharp increase in trafficking activity, with ketamine seizures increasing by 349% between 2017 and 2022. Medically, ketamine has long been used as an anesthetic and, at lower doses, is prescribed for chronic pain, suicidality, and treatment-resistant depression. In the U.S., intranasal esketamine is FDA-approved for depression. However, findings from earlier research by Dr. Linda Cottler (University of Florida) and Dr. Joseph Palamar (NYU) raise concerns. Palamar's group documented a consistent increase in nonmedical ketamine use and exposures between 2006 and 2019. Cottler's team, using U.S. National Poison Data System records from 2019 to 2021, noted rising poisonings involving ketamine, despite its relatively low prevalence at the time. Alarmingly, nearly 40% of those cases involved intentional misuse or suicide attempts. Palamar's 2025 follow-up study confirmed that this trend has continued through 2023. The study by Zhang et al. (2017) found that between 2000 and 2015, North American print media coverage of ketamine shifted significantly, from predominantly emphasizing its abuse potential to increasingly portraying it as a promising antidepressant treatment. From 2008 to 2015, articles were notably more likely to highlight ketamine's efficacy for treatment-resistant depression and its superiority over conventional antidepressants, suggesting that evolving media narratives may have contributed to its growing popularity and off-label clinical use (Zhang et al., 2017). Polysubstance use is also a concern. Ketamine is often co-ingested with benzodiazepines, alcohol, opioids, stimulants like cocaine, and club drugs including MDMA, LSD, and GHB. This pattern of co-use dramatically raises the risk of overdose and death, particularly when injected. Cottler and colleagues stressed that ketamine poisonings rarely occur in isolation but are part of a larger polysubstance crisis. Ketamine is also prescribed off-label for pain conditions such as Complex Regional Pain Syndrome (CRPS), where transient benefits may be tied to NMDA receptor blockade. These alternative applications, while promising in some cases, highlight unresolved questions about the drug's durability, mechanism of action, and potential for misuse across both psychiatric and pain-related domains. KEY INSIGHTS: Once primarily associated with recreational nightlife use, ketamine is now increasingly used in domestic settings as a self-administered "chill-out" or escapist drug. A growing number of individuals are turning to regular ketamine use as an unsupervised method of managing psychological distress, including anxiety, depression, and trauma-related symptoms. Emerging evidence links frequent ketamine exposure to serious adverse outcomes, including urological damage, cognitive and psychiatric disturbances, and a heightened risk for substance use disorders. [ABSTRACT FROM AUTHOR]
Copyright of Substance Use & Misuse is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Background: Since 2000, rates of suicide and opioid overdose have sharply increased. Approximately one-third of individuals with major depressive disorder (MDD) experience treatment-resistant depression (TRD), highlighting the urgent need for novel therapeutic approaches. Objective: This review synthesizes pivotal preclinical and clinical findings on low-dose ketamine's rapid antidepressant effects and examines proposed mechanisms underlying its therapeutic action. Methods: This is a narrative review of key contributions in the literature addressing ketamine's fast-acting antidepressant properties. Results: Low-dose ketamine rapidly alleviates depressive symptoms, including in refractory depression. Despite multiple hypotheses supported by preliminary data, there is no consensus regarding its definitive mechanism of action. Proposed mechanisms include modulation of dopamine signaling via epigenetic neuroadaptation, interactions with D1/D2 receptor systems, optogenetic activation of D1 pathways, and alterations in D2/D3 receptor availability. Conclusions: Elucidating ketamine's mechanism of action may inform the development of next-generation psychoplastogens that promote neural plasticity in TRD and unipolar MDD. However, ketamine's psychoactive properties and abuse potential, along with concerns regarding misuse and diversion, underscore the need for enhanced clinical oversight and regulatory frameworks. PREAMBLE: A recent editorial in the British Medical Journal (BMJ) highlighted a dramatic rise in non-prescribed ketamine use in the UK, with over 3,600 individuals seeking treatment for ketamine addiction in 2023–2024, an eightfold increase compared to a decade earlier. This trend is not isolated to the UK; misuse has surged across Europe and the United States. It is worth noting that as early as 2015, the BMJ cautioned against overstating ketamine's antidepressant benefits and warned of its methodological flaws and risks of misuse, warnings that appear to have been largely overlooked (Zhang & Ho, 2015). Once confined to occasional recreational use in nightlife settings, ketamine is now frequently self-administered at home, often daily, by individuals attempting to manage symptoms of anxiety, depression, PTSD, or chronic stress without medical oversight. Despite its therapeutic promise at controlled doses, ketamine carries well-established risks. A 2016 publication by one of the present authors outlined these concerns early on. The BMJ editorial affirms ketamine-associated urotoxicity, which can manifest as urinary incontinence, severe bladder pain (commonly referred to as "K-cramps"), and reduced bladder capacity, sometimes necessitating surgical intervention, including bladder removal. The editorial also reported new adverse outcomes from chronic use, including cognitive deficits, affective disturbances (e.g., anxiety, depression, psychosis), gastrointestinal complications, and renal injury. Ceban et al. (CNS Drugs, 2021) reported that while most ketamine- and esketamine-related adverse effects are mild and transient, clinicians should remain vigilant regarding potential long-term toxicity and abuse liability. Ng et al. (Psychopharmacology, 2021) further demonstrated that chronic or high-frequency ketamine exposure may lead to urothelial inflammation and bladder dysfunction, highlighting the importance of monitoring genitourinary symptoms during treatment (Ceban et al., 2021; Ng et al., 2021). Though ketamine-related fatalities remain comparatively low, the numbers are steadily rising. The drug remains accessible and inexpensive, often costing less than cocaine. DEA data show a sharp increase in trafficking activity, with ketamine seizures increasing by 349% between 2017 and 2022. Medically, ketamine has long been used as an anesthetic and, at lower doses, is prescribed for chronic pain, suicidality, and treatment-resistant depression. In the U.S., intranasal esketamine is FDA-approved for depression. However, findings from earlier research by Dr. Linda Cottler (University of Florida) and Dr. Joseph Palamar (NYU) raise concerns. Palamar's group documented a consistent increase in nonmedical ketamine use and exposures between 2006 and 2019. Cottler's team, using U.S. National Poison Data System records from 2019 to 2021, noted rising poisonings involving ketamine, despite its relatively low prevalence at the time. Alarmingly, nearly 40% of those cases involved intentional misuse or suicide attempts. Palamar's 2025 follow-up study confirmed that this trend has continued through 2023. The study by Zhang et al. (2017) found that between 2000 and 2015, North American print media coverage of ketamine shifted significantly, from predominantly emphasizing its abuse potential to increasingly portraying it as a promising antidepressant treatment. From 2008 to 2015, articles were notably more likely to highlight ketamine's efficacy for treatment-resistant depression and its superiority over conventional antidepressants, suggesting that evolving media narratives may have contributed to its growing popularity and off-label clinical use (Zhang et al., 2017). Polysubstance use is also a concern. Ketamine is often co-ingested with benzodiazepines, alcohol, opioids, stimulants like cocaine, and club drugs including MDMA, LSD, and GHB. This pattern of co-use dramatically raises the risk of overdose and death, particularly when injected. Cottler and colleagues stressed that ketamine poisonings rarely occur in isolation but are part of a larger polysubstance crisis. Ketamine is also prescribed off-label for pain conditions such as Complex Regional Pain Syndrome (CRPS), where transient benefits may be tied to NMDA receptor blockade. These alternative applications, while promising in some cases, highlight unresolved questions about the drug's durability, mechanism of action, and potential for misuse across both psychiatric and pain-related domains. KEY INSIGHTS: Once primarily associated with recreational nightlife use, ketamine is now increasingly used in domestic settings as a self-administered "chill-out" or escapist drug. A growing number of individuals are turning to regular ketamine use as an unsupervised method of managing psychological distress, including anxiety, depression, and trauma-related symptoms. Emerging evidence links frequent ketamine exposure to serious adverse outcomes, including urological damage, cognitive and psychiatric disturbances, and a heightened risk for substance use disorders. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Substance Use & Misuse is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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