Ketamine

🧠 Depression

1. 🆕 📄 Title: Esketamine Monotherapy in Adults With Treatment‑Resistant Depression, JAMA Psychiatry, 2025

👥 Authors: Adam Janik, Xin Qiu, Rosanne Lane, et al.
🔗 Link: Read Full Study – https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2836115?

🧠 Summary: This Phase 4, double-blind, placebo-controlled trial is the first to assess esketamine as monotherapy (without oral antidepressants) in adults with treatment-resistant depression (TRD). After discontinuing prior antidepressants, 378 patients were randomized to receive esketamine nasal spray (56 mg or 84 mg) or placebo, twice weekly for 4 weeks. The primary outcome was change in MADRS depression scores at Day 28.

📊 Results

• Rapid onset of antidepressant effects within 24 hours (Day 2)

• Sustained benefit at Day 28 for both doses:

  • Day 2 MADRS reduction vs placebo:

    • 56 mg: –3.8 points (p = .004)

    • 84 mg: –3.4 points (p = .006)

  • Day 28 MADRS reduction vs placebo:

    • 56 mg: –5.1 points (p < .001; ES = 0.48)

    • 84 mg: –6.8 points (p < .001; ES = 0.63)

• Adverse events were mostly mild and transient:

  • Nausea (24.8%), dissociation (24.3%), dizziness (21.7%), headache (19.0%)

• No serious safety concerns or treatment-related deaths reported

✅ Conclusion: Esketamine nasal spray effectively reduced depressive symptoms within 24 hours and maintained efficacy over 4 weeks without the need for adjunctive antidepressants. This trial supports esketamine monotherapy as a fast-acting and viable option for patients unable to tolerate or benefit from oral medications.

2. 🆕 📄 Title: Esketamine Nasal Spray versus Extended‑Release Quetiapine in Treatment‑Resistant Depression: ESCAPE‑TRD Secondary Analysis

👥 Authors: Andreas Reif, Veena Popova, et al. (2025)

🔗 Link: psychiatryonline.org+9pubmed.ncbi.nlm.nih.gov+9pubmed.ncbi.nlm.nih.gov+9cambridge.org+2pubmed.ncbi.nlm.nih.gov+2psychiatryonline.org+2

🧠 Summary: A phase 3b, randomized, open-label, rater-blinded trial (ESCAPE‑TRD) compared esketamine nasal spray + SSRI/SNRI (n=165) with extended-release quetiapine + SSRI/SNRI (n=156) over 32 weeks, focusing on work productivity, remission rates, relapse prevention, and cost impact.

• Work impairment improved significantly more with esketamine:

  • Week 8: 30.3 vs. 17.3 percentage‑point reduction (mean difference = 13.0 pp)

  • Week 32: 45.3 vs. 32.5 pp (MD = 12.7 pp) 

  • Weekly cost savings: ≈$156–$153 favoring esketamine

• Remission rates (MADRS ≤10) by Week 8:

  • Esketamine: 27.1%

  • Quetiapine: 17.6% (p=0.003)

  • Sustained remission through Week 32: 21.7% vs. 14.1% (p=0.009)

• Financial benefit: Greater work productivity gains and societal cost reductions with esketamine.

• Safety outcomes: No new adverse safety signals. Both treatments were well tolerated; fewer discontinuations due to side effects in the esketamine group.

✅ Conclusion: Esketamine nasal spray not only outperformed quetiapine XR in remission and sustained recovery but also improved work productivity and reduced indirect costs. This real-world–style comparison strengthens the case for esketamine as a superior stage‑2 intervention in treatment-resistant depression.

📚 Citation: Reif A, Popova V, Martinez R, Aadamsoo K, Bitter I, Gálvez V, Pungor K, Rancans E, Žemaitis M, Schlaepfer TE, Daly EJ, Wajsbrot DB, Lim P, Manji HK, Drevets WC, Singh JB. Esketamine nasal spray versus extended-release quetiapine in treatment-resistant depression: ESCAPE-TRD secondary analysis. International Journal of Neuropsychopharmacology. 2025;28(4):307–317.

3. 🆕 📄 Title: Efficacy of Intranasal Esketamine in Treatment-Resistant Depression: A Six‑Month Real‑World Follow‑Up Study of Depressive Symptoms, Hopelessness, and Suicide Risk, Human Psychopharmacology 2025
   👥 Authors: Maurizio Pompili, Maria Anna Trocchia, Ludovica Longhini, Eva Dispenza, Cristina Di Legge, Salvatore Sarubbi, Denise Erbuto, Isabella Berardelli
   🔗 Link: PubMed PMID 40631808 

🧠 Summary: This prospective, real-world study followed 21 adults with treatment-resistant depression over 6 months of intranasal esketamine treatment combined with standard antidepressants. The study assessed changes in clinician-rated (MADRS), patient-reported (BDI) depressive symptoms, hopelessness (BHS), and suicide risk (C-SSRS) at baseline, 3, and 6 months.

📊 Results:

• Depressive symptoms: Significant reductions in both MADRS and BDI scores at 3 months and sustained at 6 months

• Suicidal ideation: Marked decrease in the presence of suicidal thoughts from baseline to 6 months

• Hopelessness: BHS scores showed notable improvement over time 

✅ Conclusion: Intranasal esketamine demonstrated real-world effectiveness by significantly reducing depressive symptoms, hopelessness, and suicidal ideation over a six-month period in treatment-resistant depression patients. These findings support its sustained use in outpatient contexts.

📚 Citation: Pompili M, Trocchia MA, Longhini L, Dispenza E, Di Legge C, Sarubbi S, Erbuto D, Berardelli I. Efficacy of intranasal esketamine in treatment-resistant depression: A six-month real-world follow-up study of depressive symptoms, hopelessness, and suicide risk. Human Psychopharmacology: Clinical and Experimental. 2025;40(4):e2875.

4. 📄 Title: Ketamine vs Electroconvulsive Therapy for Nonpsychotic Treatment‑Resistant Major Depression (ELEKT‑D Trial, Secondary Analysis)

👥 Authors: Manish K. Jha, Sophia T. Wilkinson, Gerard Sanacora, James W. Murrough, et al. (2024)

🔗 Link: Read full study on PubMed 

🧠 Summary: This secondary analysis of the randomised, open‑label ELEKT‑D trial (n = 365) compared 6 IV ketamine infusions (0.5 mg/kg) versus 9 ECT sessions over 3 weeks in patients with nonpsychotic, treatment-resistant depression (TRD)

Key findings:

• Ketamine was noninferior to ECT overall; 55.4% of ketamine patients versus 41.2% of ECT patients responded (≥ 50% QIDS‑SR16 reduction), with a 14.2% difference favoring ketamine (95% CI: 3.9–24.2; noninferior) 

• Subgroup analysis:

  • Outpatients and those with moderately severe depression (QIDS-SR16 ≤ 20) benefitted more from ketamine.

  • Inpatients and those with very severe depression (QIDS‑SR16 > 20) saw faster early improvement with ECT, though end-of-study outcomes were similar across groups

• Cognitive safety: Ketamine showed no significant memory impairment, while ECT was associated with a notable decline in recall during treatment (e.g., delayed HVLT‑R score drop of -9.7 vs −0.9)

✅ Conclusion: For adults with nonpsychotic TRD, IV ketamine is an effective and cognitively safer alternative to ECT, especially suitable for outpatients and moderate depression severity. However, ECT may still be preferred for rapid response in severe or inpatient cases. These results aid in personalized treatment planning and shared decision-making.

📚 Citation: Jha MK, Wilkinson ST, Sanacora G, De La Garza A, Cote TR, Marton T, Kraus C, Kautz M, Cooper CM, Carpenter LL, Conway CR, Husain MM, Trivedi MH, Murrough JW. Ketamine vs electroconvulsive therapy for nonpsychotic treatment-resistant major depression: Secondary analysis of the ELEKT-D randomized clinical trial. JAMA Psychiatry. 2024;81(6):567–576.

5. 📄 Title: Efficacy and Safety of Ketamine and Esketamine for Unipolar and Bipolar Depression: Overview of Systematic Reviews and Meta‑Analyses

👥 Authors: Alessandro Rodolico, Pierfelice Cutrufelli, et al. (2024)

🔗 Link: Read Full Study on PubMed 

🧠 Summary: This 2024 overview of 26 systematic reviews and 44 RCTs (total N = 3,316) evaluated both ketamine (all forms—IV, IM, IN) and esketamine in adults with unipolar and bipolar depression, including TRD and cases with suicidal ideation.

Key findings: Both compounds were found to be effective and generally well tolerated, providing rapid relief of depressive symptoms and suicidal thinking 

• Despite consistent positive outcomes, evidence quality was rated as low, due to methodological limitations in the underlying studies 

• The overview couldn’t reliably distinguish differences in efficacy or safety between ketamine and esketamine, or between unipolar vs. bipolar depression 

✅ Conclusion: Both ketamine and esketamine demonstrate strong and rapid antidepressant effects, including reductions in suicidal ideation. However, the current low certainty of evidence underscores the need for more rigorous, high-quality trials to guide clinical practice and policy.

📚 Citation: Rodolico A, Cutrufelli P, Quattrone D, Naro A, De Luca R, Vetri L, Provenzano G, Bonanno L, Russo A, Signorelli MS, Aguglia E, Calabrò RS. Efficacy and safety of ketamine and esketamine for unipolar and bipolar depression: Overview of systematic reviews and meta-analyses. CNS Drugs. 2024;38(2):103–120.

6. 📄 Title: Effects of Low‑Dose Ketamine Infusion on the Positive and Negative Domains of Hopelessness and Suicidal Thoughts

👥 Authors: Lin W‑C., Chen M‑H., Su T‑P., Li C‑T., Wu H‑J., Tsai S‑J., Bai Y‑M., Mao W‑C., Tu P‑C. (2024)

🔗 Link: Read Full Study on PubMed

🧠 Summary: In this randomized, double-blind, midazolam-controlled trial, 84 adults with treatment-resistant depression and strong suicidal ideation received a single 0.5 mg/kg ketamine infusion or 0.045 mg/kg midazolam. Hopelessness and suicidal symptoms were assessed at 240 minutes and Days 2, 3, 7, and 14.

• Within 4 hours, the ketamine group showed a significant reduction in hopelessness (Beck Hopelessness Scale negative domain, P = .031) compared to midazolam 

• By Day 2, ketamine recipients had improved scores on both positive and negative suicidal thoughts inventory (PANSI; P = .008, .015) 

• While the immediate anti-hopelessness effect was brief (~4 hours), positive effects on suicidal ideation persisted through Days 2–7 

✅ Conclusion: A single low-dose ketamine infusion rapidly reduces feelings of hopelessness and suicidal thoughts in heavily symptomatic TRD patients. These findings highlight ketamine’s urgent potential for crisis intervention, though the effects are short-lived and warrant further study into duration, mechanisms, and dosing strategies.

📚 Citation: Lin W-C, Chen M-H, Su T-P, Li C-T, Wu H-J, Tsai S-J, Bai Y-M, Mao W-C, Tu P-C. Effects of low-dose ketamine infusion on the positive and negative domains of hopelessness and suicidal thoughts. Journal of Affective Disorders. 2024;349:514–520. 

7. 📄 Title: A Randomized, Double‑Blind, Placebo‑Controlled Pilot Trial of the Acute Antisuicidal and Antidepressant Effects of Intranasal (R,S)-Ketamine in Severe Unipolar and Bipolar Depression With and Without Comorbid Alcohol Use Disorder

👥 Authors: Gregory H. Jones, Courtney M. Vecera, Ana C. Ruiz, Hanjing E. Wu, Sophia I. McInturff, Maria J. Orejarena, Kacy A. Smith, Jair C. Soares, Carlos A. Zarate, Scott D. Lane, Rodrigo Machado‑Vieira (2024)

🔗 Link: Read Full Study on PubMed 

🧠 Summary: In this double‑blind, placebo‑controlled pilot study, 84 inpatients (unipolar or bipolar depression) with suicidal ideation and past attempts received a single 50 mg dose of intranasal R,S‑ketamine or saline placebo.

• Primary outcome (suicidal ideation): No significant overall difference between ketamine and placebo (P=.36), though a trend suggested ketamine had stronger effects in those with comorbid alcohol use disorder.

• Secondary outcome (depression): Ketamine led to significantly greater reductions in MADRS scores (P=.03), across both groups—with and without AUD.

• In the ketamine group without AUD, improvements in depression correlated strongly with reduced suicidal thoughts (r=0.927, P=.023), an effect not observed in participants with AUD.

✅ Conclusion: A single 50 mg dose of intranasal racemic ketamine was rapidly antidepressant and well-tolerated in severely depressed inpatients. While it didn’t significantly outperform placebo on suicidality overall, it showed promise, especially in non-AUD patients. Larger controlled trials are warranted to fully explore its acute anti-suicidal potential.

📚 Citation: Jones GH, Vecera CM, Ruiz AC, Wu HE, McInturff SI, Orejarena MJ, Smith KA, Soares JC, Zarate CA, Lane SD, Machado-Vieira R. A randomized, double-blind, placebo-controlled pilot trial of the acute antisuicidal and antidepressant effects of intranasal (R,S)-ketamine in severe unipolar and bipolar depression with and without comorbid alcohol use disorder. International Journal of Neuropsychopharmacology. 2024;27(4):337–347. 

8. 🎖️📄 Title: Clinical Outcomes of Intravenous Ketamine Treatment for Depression in the VA Health System

👥 Authors: Dara Ganoczy, Mohini Ranganathan, William S. Gilmer, Paul N. Pfeiffer, Ilse R. Wiechers, Avinash Hosanagar, Brian Martis, Jamarie Geller, Jennifer Jagusch, John Carty, Fe Erlita D. Festin (2024)

🔗 Link: https://www.psychiatrist.com/jcp/clinical-outcomes-intravenous-ketamine-for-depression-va-health-system/

🧠 Summary: This observational study analyzed electronic records of 215 veterans diagnosed with treatment-resistant depression (TRD) who received repeated IV ketamine infusions over 12 months within the VA system:

• Baseline PHQ‑9: Mean score of 18.6, with an average of 6 prior antidepressant treatments.

• Infusion Frequency: Began biweekly (~every 5 days), tapering to monthly by month 5; patients received a mean of 18 infusions over one year

• Efficacy at 6 weeks:

  • 26% of veterans achieved ≥50% reduction in PHQ‑9 (“response”)

  • 15% reached remission (PHQ‑9 ≤5) 

• Sustained benefit: Improvements in depressive symptoms persisted through weeks 12 and 26 

• No demographic or comorbidity factors predicted 6-week outcomes—meaning benefits occurred consistently across diverse patient profiles 

✅ Conclusion: In real-world VA settings, repeated IV ketamine infusions produced durable antidepressant effects in a subset of Veterans with TRD. Though only ~1 in 4 responded and ~1 in 7 fully remitted, these improvements were sustained with tapered maintenance. More research is needed to identify predictors of response and refine long-term protocols.

📚 Citation: Ganoczy D, Ranganathan M, Gilmer WS, Pfeiffer PN, Wiechers IR, Hosanagar A, Martis B, Geller J, Jagusch J, Carty J, Festin FE. Clinical outcomes of intravenous ketamine treatment for depression in the VA health system. Journal of Affective Disorders. 2024;344:341–347. 

🕊️ Suicide/End Of Life

1. 🆕 📄 Title: Offering Psychedelic Treatments Before Assisted Dying for Psychiatric Conditions, JAMA Psychiatry, 2025
   👥 Authors: Christopher Poppe, PhD; Jan Christoph Bublitz, PhD, LLB; Dimitris Repantis, MD
   🔗 Link: (JAMA Psychiatry, 2025)

🧠 Summary:  This perspective article addresses the ethical and clinical implications of offering psychedelic-assisted therapy to individuals who are seeking assisted dying for psychiatric conditions—a legal option in some jurisdictions. The authors argue that psychedelic interventions, such as those involving psilocybin or ketamine, should be systematically explored and offered as part of comprehensive psychiatric care prior to granting approval for medical assistance in dying (MAID).

They note that psychedelics have demonstrated rapid-acting, durable antidepressant and anti-suicidal effects in clinical studies, and thus may help reduce the desire for assisted dying among patients with chronic psychiatric suffering. The piece advocates for policy changes and ethical guidelines that require access to evidence-based psychedelic treatments before finalizing MAID for mental illness.

📊 Key Points

• Psychedelics may offer renewed hope, meaning, and relief even in patients with long-standing treatment-resistant conditions.

• Several studies suggest potential anti-suicidal effects, warranting their use before irreversible end-of-life decisions.

• The authors call for systematic inclusion of psychedelic treatment trials before approving MAID in psychiatric cases.

✅ Conclusion: Given the growing evidence for psychedelic therapies in alleviating treatment-resistant depression and suicidality, these interventions should be mandated as part of the clinical pathway before permitting assisted dying for psychiatric conditions. This approach may preserve life, restore dignity, and ensure ethical integrity in psychiatric end-of-life care.

2. 📄 Title: U.S. Suicide Deaths Reach Record High, The Psychiatrist (2024)
   👥 Author: The Psychiatrist Staff
   🔗 Link: Read Full Article on The Psychiatrist

🧠 Summary:  This article reports on CDC data showing that suicide deaths in the United States reached an unprecedented high in 2022, with nearly 50,000 Americans lost to suicide. The article emphasizes the urgent need for faster-acting and more effective treatments, specifically highlighting ketamine as a promising intervention for reducing suicidal ideation. Despite increased awareness of the mental health crisis, current treatment options remain slow and inadequate for many individuals in acute distress.

📊 Results:  In 2022, 49,449 suicide deaths were recorded—a 2.6% increase from the previous year, and the highest number in U.S. history. Suicide rates rose notably among adults over 45. The article stresses that many people experiencing suicidal thoughts are not helped fast enough by conventional antidepressants. Ketamine, with its rapid-acting antidepressant and anti-suicidal properties, is presented as one of the most promising innovations, with mounting evidence for use in emergency psychiatric care and treatment-resistant cases.

✅ Conclusion:  The worsening suicide epidemic highlights the failure of current mental health systems to address urgent needs. The article calls for accelerated adoption of novel treatments like ketamine, which may offer rapid and potentially life-saving relief for people at high risk of suicide. Policymakers and clinicians are urged to expand access to ketamine and other emerging therapies backed by clinical evidence.

🧪 Addiction

1. 📄 Title: Ketamine Treatment for Alcohol Use Disorder: A Systematic Review, Cureus 2023
👥 Authors: Michael Kelson, Justin M. Burnett, Amy Matthews, Tony Juneja
🔗 Link: PubMed: 37273364 Psychedelic Support+8PubMed+8Wiley Online Library+8Psychedelic Support+2Baylor College of Medicine+2Wiley Online Library+2

🧠 Summary: This systematic review assessed 11 human studies (n=854), including RCTs, cohort studies, and case series, on ketamine interventions for alcohol use disorder (AUD), heavy drinking, and alcohol withdrawal across the USA, UK, and Russia. It examined outcomes like abstinence, consumption, craving, relapse, and withdrawal symptoms.

📊 Results: 

• Abstinence & reduced consumption were most pronounced in studies using ketamine combined with psychotherapy 

• Withdrawal symptom reduction and craving showed mixed findings across studies 

• Most data indicated safety and feasibility, but definitive conclusions were limited by heterogeneous protocols and small sample sizes.

✅ Conclusion: Ketamine—especially when combined with psychotherapy—appears promising for promoting abstinence and reducing drinking in individuals with AUD. However, larger, robust clinical trials are needed to clarify dosing strategies, efficacy, and long-term safety 

📚 Citation: Kelson M, Burnett JM, Matthews A, Juneja T. Ketamine treatment for alcohol use disorder: A systematic review. Cureus. 2023;15(10):e46913.

2. 📄 Title: The Ketamine for Reduction of Alcohol Relapse (KARE) Trial, The American Journal of Psychiatry, 2022
👥 Authors: Celia J. A. Morgan, Amy M. Hardy, et al.
🔗 Link: Read Full Study

🧠 Summary: The KARE trial was a phase 2, double-blind, placebo-controlled clinical study examining the effectiveness of ketamine-assisted therapy in reducing relapse rates in individuals with alcohol use disorder (AUD). Participants were randomized to receive either three infusions of ketamine plus psychotherapy or placebo plus alcohol education.

📊 Results:

• Primary outcome: Total days of abstinence in 6 months post-treatment.

• The ketamine group showed significantly more abstinent days compared to the placebo group (median of 162 vs. 131 days).

• 87% abstinence at 6-month follow-up in ketamine + therapy group, vs. 75% in placebo group.

• Ketamine also reduced cravings and depression symptoms more effectively than placebo.

✅ Conclusion: Ketamine, when combined with psychological therapy, may significantly reduce relapse in patients with alcohol use disorder and could represent a novel pharmacological-psychotherapeutic intervention for addiction treatment.

📚 Citation: Grabski, M., McAndrew, A., Lawn, W., Marsh, B., Raymen, L., Morgan, C. J. A., Nutt, D. J., Curran, H. V., & Freeman, T. P. (2022). Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder. The American Journal of Psychiatry, 179(3), 152–162. https://doi.org/10.1176/appi.ajp.2021.21010089 

3. 📄 Title: Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review
👥 Authors: Jennifer L. Jones, Camilo F. Mateus, Robert J. Malcolm, Kathleen T. Brady & Sudie E. Back
🔗 Link: Frontiers in Psychiatry, 2018;9:277, doi:10.3389/fpsyt.2018.00277 

🧠 Summary: This systematic review examined ketamine’s therapeutic potential for alcohol, cocaine, opioid, and cannabis use disorders by analyzing human clinical trials up to January 2018. It covered seven completed studies—two on alcohol, two on cocaine, and three on opioids—as well as six ongoing randomized controlled trials (including emerging protocols targeting alcohol, cocaine, opioids, and cannabis).

📊 Results:

• Alcohol & Opioids: Single high-dose ketamine (2 mg/kg IM) combined with therapy showed significant improvements in abstinence rates lasting up to 2 years post-treatment, though these lacked placebo controls 

• Cocaine: Studies demonstrated reductions in craving, enhanced motivation to quit, and decreased cocaine use, but were limited by small participant numbers and brief follow-ups 

• Ongoing Trials: Six RCTs were identified—targeting alcohol use disorder, cocaine use disorder (with MET + MBRP), opioid detoxification, and cannabis dependence—examining various dosing regimens including IM and IV ketamine.

✅ Conclusion: Ketamine shows broad potential to support abstinence and reduce cravings across multiple substance use disorders. While early results are promising, most studies are small-scale and lack rigorous controls. The rise of contemporary RCTs—especially those integrating psychosocial therapy—marks a critical step toward establishing ketamine as a viable treatment modality in addiction medicine

📚 Citation: Jones JL, Mateus CF, Malcolm RJ, Brady KT, Back SE. Efficacy of ketamine in the treatment of substance use disorders: A systematic review. Frontiers in Psychiatry. 2018;9:277. 

4. 📄 Title: Adjunctive Ketamine Infusion for Benzodiazepine-Resistant Alcohol Withdrawal
👥 Authors: Wong A., Benedict N., et al.
🔗 Link: https://pubmed.ncbi.nlm.nih.gov/25325907/
🧠 Summary: Retrospective single-center study (N=23) in medical ICU for severe alcohol withdrawal (AWS): patients received adjunctive ketamine infusion (~0.2 mg/kg/hr) following failed benzodiazepines.
📊 Results:

• Median benzodiazepine requirement dropped; AWS severity scales remained <10.

• No AWS complications (e.g., DTs, seizures) post-ketamine; trends toward reduced benzodiazepine use at 12 & 24 h.

✅ Conclusion: Ketamine appears safe and may reduce benzodiazepine needs in severe AWS; however, lack of controls and adjunct therapy confounds limit definitive conclusions.

📚 Citation: Wong A, Benedict NJ, Armahizer MJ, Dasta JF, Anger KE. Adjunctive ketamine infusion for benzodiazepine-resistant alcohol withdrawal. Annals of Pharmacotherapy. 2015;49(1):14–19.

5. 📄 Title: The Effects of Sub‑Anesthetic Ketamine Infusions on Motivation to Quit and Cue‑Induced Craving in Cocaine‑Dependent Research Volunteers
👥 Authors: Elias Dakwar, Frances Levin, et al.
🔗 Link: PubMed 24035344 / PMC PMC4105157 periodicos.ufsm.br+6pmc.ncbi.nlm.nih.gov+6sciencedirect.com+6
🧠 Summary: This randomized, placebo-controlled, crossover trial tested two sub-anesthetic ketamine infusions (0.41 mg/kg and 0.71 mg/kg) versus lorazepam in eight non-treatment-seeking cocaine-dependent individuals. Effects were measured 24 hours after each infusion.

📊 Results:

• Motivation (URICA): Ketamine 0.41 mg/kg produced a 3.9-point increase in readiness-to-change score (p = 0.012), translating to ~60% gain over baseline, significantly outperforming lorazepam

• Cue-Induced Craving (VAS): Both ketamine doses led to significant reductions in craving compared to control (p = 0.012); the second dose yielded further lowering of craving

• Tolerance: Infusions were well tolerated with no serious adverse events reported

✅ Conclusion: Single sub-anesthetic doses of ketamine significantly increased motivation to quit cocaine and reduced cue-induced craving 24 hours post-treatment. These promising preliminary findings support further clinical trials to evaluate ketamine’s potential in real-world cocaine use disorder treatment.

📚 Citation: Dakwar E, Levin F, Hart CL, Basaraba CN, Choi CJ, Nunes EV. The effects of sub-anesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers. Biological Psychiatry. 2014;76(1):40–46. 

6. 📄 Title: Ketamine Use: A Review
👥 Authors: Morgan CJ, Curran HV
🔗 Link: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1360-0443.2011.03576.x
🧠 Summary: This 2012 narrative review in Addiction covers ketamine’s broad pharmacological and clinical profile, including its off-label psychiatric applications. The authors focus in part on ketamine’s emerging role in the treatment of substance use disorders (SUDs)—including alcohol, opioids, and cocaine.

• Cocaine: Multiple RCTs show that ketamine infusions significantly reduce cocaine self-administration and increase abstinence rates compared to midazolam. One trial reported greater motivation to quit and longer abstinent periods in ketamine-treated patients.

• Opioids: Ketamine paired with existential psychotherapy enhanced opioid abstinence, reduced withdrawal symptoms, and improved treatment retention rates. One study also noted lower pain scores and decreased need for rescue medications post-anesthesia.

• Alcohol: Ketamine-assisted therapy led to 65.8% 1-year abstinence, compared to just 24% in controls, and was associated with reduced benzodiazepine use in alcohol withdrawal treatment.

• Cannabis: Less data was available, but early indications support possible benefit in reducing problematic use.

🧪 Ongoing Research: Current trials are exploring ketamine-assisted therapy in combination with mindfulness-based therapy, motivational enhancement therapy (MET), and other integrative modalities, reflecting a growing interest in protocol customization.

✅ Conclusion: This early review helped position ketamine as a potentially powerful tool for treating various substance use disorders. It highlights promising preliminary data across multiple addictive substances, laying groundwork for a decade of deeper investigation.

📚 Citation: Morgan CJ, Curran HV. Ketamine use: A review. Addiction. 2012;107(1):27–38.

7. 📄 Title: Single vs. Multiple Ketamine-Assisted Psychotherapy Sessions for Heroin Dependence: 1-Year Abstinence Rates
👥 Authors: Evgeny M. Krupitsky, Andrei M. Burakov, et al.
🔗 Link: Based on J Psychoactive Drugs 2007 Mar;39(1):13–19 (PubMed 17523581)
🧠 Summary: 59 recently detoxified heroin-dependent participants received 2 mg/kg IM ketamine alongside existential psychotherapy; randomized to either one session + monthly counseling or two ketamine-guided sessions.
📊 Results: At 1-year follow-up, 50% of multi-session participants remained abstinent vs. 22.2% of the single-session group.

✅ Conclusion:  Adding a second ketamine-guided psychotherapy session significantly improved long-term heroin abstinence, suggesting benefit from repeated dosing.
📚 Citation: Krupitsky EM, Burakov AM, Dunaevsky IV, Romanova TN, Slavina TY, Grinenko AY. Single versus repeated sessions of ketamine-assisted psychotherapy for people with heroin dependence: A randomized trial. Journal of Psychoactive Drugs. 2007;39(1):13–19.

8. 📄 Title: Effect of Subanesthetic Ketamine on Physiological Markers During Rapid Opioid Antagonist Induction
👥 Authors: Jovaisa T., Tuncer R., et al. (2006) [first author may vary]
🔗 Link: PubMed 16963828
🧠 Summary: In a randomized controlled trial of 58 opioid-dependent adults undergoing rapid opioid antagonist induction under general anesthesia, participants received ketamine (0.5 mg/kg/h) vs. placebo (saline).
📊 Results:

• Ketamine significantly blunted increases in blood pressure, pulse, cortisol, and withdrawal severity (OOWS/SOWS) during early withdrawal.

• Required less adjunctive clonazepam and carbamazepine.

✅ Conclusion: Subanesthetic ketamine infusion can attenuate the physiological and subjective symptoms of precipitated opioid withdrawal, suggesting it may be valuable in anesthesia-assisted detoxification protocols.

📚 Citation: Jovaisa T, Laurinenas G, Vosylius S, Sipylaite J, Badaras R, Ivaskevicius J. Effect of subanesthetic ketamine on physiological parameters during rapid opioid antagonist-induced detoxification. Journal of Clinical Anesthesia. 2006;18(8):596–602.

9. 📄 Title: Ketamine Psychedelic Therapy for Heroin Addiction: Immediate Effects and Two‑Year Follow‑Up
👥 Authors: Evgeny M. Krupitsky, Andrei M. Burakov, Irina V. Dunaevsky, Tatiana N. Romanova, Tymur Y. Slavina, Anastasia Y. Grinenko
🔗 Link: PubMed 12495789
🧠 Summary: A randomized double-blind clinical trial compared high-dose (2 mg/kg) vs. low-dose (0.2 mg/kg) intramuscular ketamine, each administered with existential psychotherapy, in 70 recently detoxified heroin-dependent inpatients.
📊 Results:

• Abstinence: High-dose group showed significantly higher complete heroin abstinence at 1 and 2 years (24% & 17%) compared to low-dose (6% & 2%), p < 0.05.

• Craving & emotional changes: High-dose treatment produced greater and more sustained reductions in craving and enhanced nonverbal emotional attitudes.

✅ Conclusion: Ketamine-assisted psychotherapy, especially at psychedelic doses, offers sustained benefit in heroin addiction treatment—supporting psychotherapy-enhanced ketamine as a promising intervention.

📚 Citation: Krupitsky EM, Burakov AM, Dunaevsky IV, Romanova TN, Slavina TY, Grinenko AY. Ketamine psychedelic therapy for heroin addiction: Immediate effects and two-year follow-up. Journal of Psychoactive Drugs. 2002;34(2):191–196.

10. 📄 Title: Ketamine-Existential Psychotherapy vs. Standard Detox for Alcohol Dependence
👥 Authors: Krupitsky E.M. et al. (Russian team from the 1980s)
🔗 Link: https://pubmed.ncbi.nlm.nih.gov/9250944/
🧠 Summary: In a two-arm, case-control design with 111 treatment-seeking alcohol-dependent individuals (ages 23–56) post-detox, one group received a single 2.5 mg/kg IM ketamine dose combined with existential psychotherapy; controls received standard follow-up.
📊 Results:

• 1‑year abstinence: 65.8% (73/111) in the ketamine group vs. 24% (24/100) in controls.

• 2‑year abstinence: 40.7% in ketamine group; comparison group only followed for 1 year.

✅ Conclusion: Ketamine-assisted psychotherapy markedly increased abstinence rates at one year compared to usual care, though design limitations (non-randomized, selection bias) limit causal inference.

📚 Citation: Krupitsky EM, Grinenko AY. Ketamine–existential psychotherapy for the treatment of alcohol dependence: A randomized controlled trial. Journal of Psychoactive Drugs. 1997;29(2):111–118.

💥 Trauma/PTSD

1. 📄 Title: Combining Ketamine Infusions and Written Exposure Therapy for Chronic PTSD, J Clin Psychiatry 2025

👥 Authors: Adriana Feder, Oneysha Brown, Sarah B. Rutter, Leah Cahn, Jessica R. Overbey, Saren H. Seeley, Alex Yu, Philip A. Bonanno, Rachel A. Fremont, Andrew A. Delgado, Manish K. Jha, Sara Costi, Rachel Yehuda, Daniela Schiller, Robert H. Pietrzak, Dennis S. Charney, Denise M. Sloan, James W. Murrough

🔗 Link: PubMed: 40215385

🧠 Summary: This open-label trial combined a course of six 0.5 mg/kg IV ketamine infusions (three times per week over two weeks) with five Written Exposure Therapy (WET) sessions, beginning after the fourth infusion, in adults with chronic, moderate-to-severe PTSD. The primary endpoint was the change in Clinician Administered PTSD Scale for DSM-5 (CAPS-5) scores at 12 weeks.

📊 Results: Symptom severity: CAPS-5 mean score dropped from 41.6 (SD 6.2) at baseline to 20.8 (SD 14.8) at Week 12 (Cohen's d = 1.9 [1.0–2.8]; p < .001)
Responder rate: 9 of 13 completers (69%) achieved ≥30% CAPS-5 reduction; effects were durable in 8 participants (62%) up to 6 months.
Retention and safety: 13 of 14 participants completed all treatments; no serious adverse events were reported
✅ Conclusion: Combining repeated ketamine doses with WET appears both feasible and effective for reducing severe chronic PTSD symptoms, with large effect sizes and sustained durability. Despite sample size and open-label limitations, these preliminary findings justify urgent randomized, controlled investigations to evaluate potential synergistic benefits.

📚 Citation: Feder A, Brown O, Rutter SB, Cahn L, Overbey JR, Seeley SH, Yu A, Bonanno PA, Fremont RA, Delgado AA, Jha MK, Costi S, Yehuda R, Schiller D, Pietrzak RH, Charney DS, Sloan DM, Murrough JW. Combining ketamine infusions and written exposure therapy for chronic PTSD: A randomized clinical trial. Journal of Clinical Psychiatry. 2025;86(3):24m15182.

2. 📄 Title: A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder

👥 Authors: Adriana Feder, Sara Costi, Sarah B. Rutter, Abigail B. Collins, Usha Govindarajulu, Manish K. Jha, Sarah R. Horn, Marin Kautz, Morgan Corniquel, Katherine A. Collins, Laura Bevilacqua, Andrew M. Glasgow, Jess Brallier, Robert H. Pietrzak, James W. Murrough, Dennis S. Charney (2021)

🔗 Link: https://pubmed.ncbi.nlm.nih.gov/33397139/

🧠 Summary: This landmark randomized controlled trial investigated the effects of repeated intravenous ketamine infusions in patients with chronic posttraumatic stress disorder (PTSD). Thirty participants were randomized to receive either six ketamine infusions (0.5 mg/kg) or midazolam (psychoactive placebo) over two weeks. By the end of the treatment, the ketamine group had significantly greater reductions in PTSD symptom severity (as measured by CAPS-5) and depressive symptoms (MADRS) compared to the control group. 67% of ketamine recipients were treatment responders, versus only 20% in the placebo group. Responses were generally maintained for about four weeks post-treatment. No serious adverse events occurred, and the treatment was well tolerated. This trial provides strong evidence supporting ketamine as an effective and rapid-acting treatment for individuals with chronic PTSD, especially those who have not responded to conventional therapies.

📚 Citation: Feder A, Costi S, Rutter SB, Collins AB, Govindarajulu U, Jha MK, Horn SR, Kautz M, Corniquel M, Collins KA, Bevilacqua L, Glasgow AM, Brallier J, Pietrzak RH, Murrough JW, Charney DS. A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder. American Journal of Psychiatry. 2021;178(2):193–202.

🔁 Obsessive-Compulsive Disorder (OCD)

1. 📄 Title: Ketamine in the Treatment of Obsessive-Compulsive Disorder: A Systematic Review

👥 Authors: Igor D. Bandeira, Daniel H. Lins-Silva, Vitor B. Cavenaghi, Ingrid Dorea-Bandeira, Daniela Faria-Guimarães, Judah L. Barouh, Ana Paula Jesus-Nunes, Graziele Beanes, Lucca S. Souza, Gustavo C. Leal, Gerard Sanacora, Euripedes C. Miguel, Aline S. Sampaio, Lucas C. Quarantini (2022)

🔗 Link: Read Full Study on PubMed

🧠 Summary: This systematic review evaluated the therapeutic potential of ketamine in treating obsessive-compulsive disorder (OCD). Nine studies were included: three randomized controlled trials, two open-label trials, three case reports, and one retrospective chart review.
The results suggest that intravenous racemic ketamine may offer a rapid, though often short-lived, reduction in OCD symptoms, with effects sometimes observable after just one session.
While ketamine was generally well-tolerated, findings across studies were inconsistent, and there is currently no consensus on whether racemic ketamine, S-ketamine, or R-ketamine is more effective.
The authors note a lack of research on repeated dosing, alternative delivery methods, and combination with psychotherapy, all of which may enhance efficacy.
Ultimately, the review concludes that larger, well-controlled trials are urgently needed to clarify ketamine’s role in OCD treatment, including the development of more durable and personalized treatment strategies.

📚 Citation: Bandeira ID, Lins-Silva DH, Cavenaghi VB, Dorea-Bandeira I, Faria-Guimarães D, Barouh JL, Jesus-Nunes AP, Beanes G, Souza LS, Leal GC, Sanacora G, Miguel EC, Sampaio AS, Quarantini LC. Ketamine in the treatment of obsessive-compulsive disorder: A systematic review. Revista Brasileira de Psiquiatria. 2022;44(3):301–308.

😰 Anxiety 

1. 📄 Title: Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial

👥 Authors: Jerome H. Taylor, Angeli Landeros-Weisenberger, Catherine Coughlin, Jilian Mulqueen, Jessica A. Johnson, Daniel Gabriel, Margot O. Reed, Ewgeni Jakubovski, Michael H. Bloch (2018)

🔗 Link: Read Full Study on PubMed

🧠 Summary: This randomized, double-blind, placebo-controlled crossover trial investigated the effects of a single ketamine infusion (0.5 mg/kg IV) in 18 adults with DSM-5 diagnosed social anxiety disorder (SAD).
Participants received both ketamine and placebo in randomized order with a 28-day washout period between treatments.
The ketamine infusion led to a significantly greater reduction in social anxiety symptoms, as measured by the Liebowitz Social Anxiety Scale (LSAS), compared to placebo.
In the two weeks post-infusion:

• 33% of participants met the LSAS response threshold after ketamine (vs 0% for placebo)

• 88.9% met response criteria on a self-reported anxiety scale (VAS-Anxiety) following ketamine (vs 52.9% for placebo)

No serious adverse events were reported. These results offer proof-of-concept evidence that ketamine may be an effective, fast-acting treatment for social anxiety disorder, and support further investigation into its use for anxiety spectrum conditions.

📚 Citation: Taylor JH, Landeros-Weisenberger A, Coughlin C, Mulqueen J, Johnson JA, Gabriel D, Reed MO, Jakubovski E, Bloch MH. Ketamine for social anxiety disorder: A randomized, placebo-controlled crossover trial. Neuropsychopharmacology. 2018;43(2):325–333.

🍽️ Eating Disorders

1. 📄 Title: Ketamine as a Novel Psychopharmacotherapy for Eating Disorders: Evidence and Future Directions

👥 Authors: Anya Ragnhildstveit, Matthew Slayton, Laura Kate Jackson, Madeline Brendle, Sachin Ahuja, Willis Holle, Claire Moore, Kellie Sollars, Paul Seli, Reid Robison (2022)

🔗 Link: https://pubmed.ncbi.nlm.nih.gov/35326338/

🧠 Summary: This 2022 narrative review explores ketamine as an emerging treatment option for eating disorders (EDs), particularly in patients who have not responded to conventional approaches. The authors examine existing reports, mostly involving anorexia nervosa, suggesting that ketamine—especially when used in combination with psychotherapy—may offer meaningful symptom relief in a population that otherwise faces chronic, refractory illness.
The review discusses ketamine’s transdiagnostic potential, based on its rapid antidepressant and neuroplastic effects, and highlights its use as a primary, adjunctive, or combination treatment in both research and clinical settings.
However, current evidence is limited to case studies and small series, and more rigorous, large-scale trials are needed to establish efficacy across ED subtypes, optimize dosing, and better define safety profiles.
Overall, ketamine shows promise as a novel intervention in this high-risk population, but the field remains in early stages.

📚 Citation: Ragnhildstveit A, Slayton M, Jackson LK, Brendle M, Ahuja S, Holle W, Moore C, Sollars K, Seli P, Robison R. Ketamine as a novel psychopharmacotherapy for eating disorders: Evidence and future directions. Frontiers in Psychiatry. 2022;13:927240.

🧍‍♂️ Personality Disorders

1. 📄 Title: A Pilot Randomized Controlled Trial of Ketamine in Borderline Personality Disorder

👥 Authors: Sarah K. Fineberg, Esther Y. Choi, Rosa Shapiro-Thompson, Khushwant Dhaliwal, Eli Neustadter, Madison Sakheim, Kaylee Null, Daniel Trujillo-Diaz, Jocelyne Rondeau, Giana F. Pittaro, Jessica R. Peters, Philip R. Corlett, John H. Krystal (2023)

🔗 Link: Read Full Study on PubMed

🧠 Summary: This pilot randomized controlled trial is the first to investigate the effects of ketamine in individuals with Borderline Personality Disorder (BPD).
Twenty-two adults with BPD were randomized to receive a single infusion of either ketamine (0.5 mg/kg) or midazolam (active placebo).
The treatment was well tolerated, with ketamine producing transient dissociative symptoms that resolved within 40 minutes.
Although there were no statistically significant group differences in suicidal ideation, depression, anxiety, or core BPD symptoms, the ketamine group showed greater improvement in socio-occupational functioning by Day 14.
This improvement correlated with reductions in depression in the ketamine group, suggesting a potential secondary benefit on daily functioning even in the absence of clear mood symptom superiority.
The authors conclude that antidepressant-dose ketamine may hold promise for improving life functioning in BPD and should be further explored in larger, powered trials.

📚 Citation: Fineberg SK, Choi EY, Shapiro-Thompson R, Dhaliwal K, Neustadter E, Sakheim M, Null K, Trujillo-Diaz D, Rondeau J, Pittaro GF, Peters JR, Corlett PR, Krystal JH. A pilot randomized controlled trial of ketamine in borderline personality disorder. Journal of Personality Disorders. 2023;37(Supplement A):1–17.

🔥 Chronic Pain

1. 📄 Title: Ketamine for Acute Pain After Trauma: A Pragmatic, Randomized Clinical Trial
   👥 Authors: James M. Klugh, Thaddeus J. Puzio, Michael W. Wandling, Chelsea J. Guy‑Frank, Charles Green, Paulina B. Sergot, Samuel J. Prater, Julius Balogh, Christopher T. Stephens, Charles E. Wade, Lillian S. Kao, John A. Harvin (2024)
   🔗 Link: PubMed: 38689402 

🧠 Summary: This pragmatic, single-center randomized clinical trial (KAPT), published in Journal of Trauma and Acute Care Surgery, evaluated whether adding a sub-dissociative ketamine infusion (0.5 mg/kg/hr) to an established pill-based multimodal pain regimen (MMPR) would reduce opioid consumption in adult trauma patients over a 72-hour period.

📊 Results:

• Opioid exposure: The ketamine group had 19% lower average daily morphine milligram equivalents (MME/day) (RR 0.81; 95% CI, 0.69–0.95; posterior probability = 99%) and 20% lower total MME (RR 0.80; 0.64–0.99; posterior probability = 98%) 

• Opioid percentage: An 8% relative reduction (RR 0.92; 0.76–1.11; p‑posterior = 81%).

• Adverse events: Similar rates of arrhythmias and unplanned intubation across groups; delirium was slightly higher in ketamine recipients (11% vs. 6%) 

✅ Conclusion: A sub-dissociative ketamine infusion, added to an oral MMPR in a trauma setting, safely and effectively reduced opioid exposure in severely injured patients. This Level I evidence supports using ketamine as an adjunct to minimize opioid use during acute trauma care.

📚 Citation: Klugh JM, Puzio TJ, Wandling MW, Guy-Frank CJ, Green C, Sergot PB, Prater SJ, Balogh J, Stephens CT, Wade CE, Kao LS, Harvin JA. Ketamine for acute pain after trauma: A pragmatic, randomized clinical trial. JAMA Surgery. 2024;159(4):287–295.

2. 📄 Title: Ketamine in Fibromyalgia: A Systematic Review

👥 Authors: Jozélio Freire de Carvalho, Eduardo Pondé de Sena (2024)

🔗 Link: Read Full Study on PubMed

🧠 Summary: This systematic review evaluated the safety and effectiveness of ketamine for patients with fibromyalgia (FM) — a chronic pain condition often resistant to conventional treatments.
Only six studies met inclusion criteria, comprising a total of 115 patients, mostly women aged 23–53. Ketamine was administered intravenously in most studies (doses from 0.1 to 0.5 mg/kg) and subcutaneously in one.
Across short-term studies, patients experienced notable reductions in pain (VAS scores decreased from 59–100 mm pre-treatment to as low as 2 mm post-treatment).
However, the only study with 8-week follow-up did not show sustained improvement, indicating that ketamine's analgesic effects may be short-lived without ongoing dosing.
Side effects were common but generally mild, appearing during infusion and resolving quickly afterward.
The review concludes that ketamine appears effective and safe for short-term pain relief in FM, but larger, long-term studies are needed to assess durability and refine treatment protocols.

📚 Citation: de Carvalho JF, de Sena EP. Ketamine in fibromyalgia: A systematic review. CNS & Neurological Disorders - Drug Targets. 2024;23(2):123–128.

📚 Evidence & Citation Policy

All research summaries on this site are based on peer-reviewed studies, clinical trials, meta-analyses, and systematic reviews. Each study includes citation details with direct hyperlinks to PubMed or the publishing journal. While we strive for accuracy, readers are encouraged to review the source materials directly. This site does not offer medical advice; for treatment decisions, please consult a licensed clinician.