Therapeutic Advances in Psychopharmacology
January 1, 2020
D. Matveychuk, Rejish K Thomas, Jennifer Swainson et al.
209 citations
Ketamine, an anesthetic from the 1960s, has gained attention as a treatment for major depressive disorder, especially treatment-resistant depression, with potential anti-suicidal effects. Unlike traditional antidepressants that take weeks, ketamine can produce rapid antidepressant effects within hours. Its mechanism involves glutamate modulation through NMDA and AMPA receptors, plus activation of BDNF and mTOR pathways to enhance synaptic plasticity. This paper reviews ketamine's pharmacology, toxicology, clinical trial status, and proposed antidepressant mechanisms, along with potential biomarkers—biochemical, inflammatory, metabolic, neuroimaging, sleep-related, and cognitive—for predicting or monitoring therapeutic response.
Journal of Psychiatric Research
May 1, 2022
Tuyen T. Le, Isabel Pazos Cordero, Muhammad Youshay Jawad et al.
82 citations
Ketamine and its enantiomers show different abuse liability. Preclinical evidence indicates that (R,S)-ketamine and (S)-ketamine carry greater risk for abuse than (R)-ketamine, which at antidepressant-relevant doses in rodents appears safe with minimal liability. In clinical settings, limited studies suggest that single or repeated ketamine administrations under professional control did not lead to misuse, dependence, diversion, or gateway activity in patients with treatment-resistant depression. However, most clinical studies were retrospective and lacked systematic evaluation with validated scales. The review identified 65 eligible studies (55 preclinical, 10 clinical), with only 4 preclinical studies evaluating enantiomer abuse liability.
CNS Drugs
February 14, 2022
Jennifer Swainson, L. Klassen, Stefan Brennan et al.
42 citations
Intravenous ketamine and intranasal esketamine are used for depression but face cost and access barriers. Non-parenteral racemic ketamine (oral, sublingual, intranasal) might improve access, though evidence is limited. Concerns about ketamine's addictive potential have not been examined against available evidence. The authors argue that ketamine misuse risks are similar to those of stimulants or benzodiazepines, and prescribing should balance patient access with misuse concerns. A consortium of mood disorder specialists considers non-parenteral ketamine a reasonable option for select treatment-resistant depression cases and provides practical prescribing recommendations.
Frontiers in psychiatry
January 1, 2023
Carson Chrenek, Bryan Duong, Atul Khullar et al.
23 citations
Intravenous ketamine and intranasal esketamine are effective for treatment-resistant depression but are limited by cost, availability, and monitoring requirements. A literature review up to June 2023 and a community case study from two public hospital sites in Edmonton, Canada, describe how evidence on ketamine for treatment-resistant depression can be applied in real-world settings. The paper synthesizes knowledge on off-label racemic ketamine versus FDA-approved esketamine, dosing, safety, and long-term maintenance. To overcome cost barriers, public programs may incorporate sublingual or intranasal ketamine. Three such sustainable treatment models are described, though large-scale randomized trials and long-term outcome data remain lacking.
Psychiatry research
October 1, 2024
Gilmar Gutierrez, Jennifer Swainson, Nisha Ravindran et al.
17 citations
Both intravenous ketamine and intranasal esketamine significantly reduce depressive symptoms and suicidal ideation in people with treatment-resistant major depressive disorder. In a multi-site observational study of 53 patients, those receiving IV ketamine (26 patients, average age 52.8) and those receiving IN esketamine (27 patients, average age 43.9) showed similar improvements in depression severity and suicidal thoughts. Side effects were mild and temporary, with no significant difference in risk between the two treatments. The findings suggest both therapies are effective and well tolerated for treatment-resistant depression.
Frontiers in psychiatry
January 1, 2022
Ryan Yip, Jennifer Swainson, Atul Khullar et al.
13 citations
Ketamine is increasingly used for treatment-resistant depression, but its intravenous administration often causes transient high blood pressure. Current psychiatric guidelines recommend aggressive monitoring and treatment of these hypertensive episodes. This review argues that those guidelines should be updated to align with standard best practices for managing hypertension, distinguishing between hypertensive emergency and asymptomatic hypertensive urgency. Adopting such an updated protocol could make ketamine therapy safer and more accessible for patients with depression.
Journal of substance use and addiction treatment
August 1, 2025
Reinhard Janssen-Aguilar, Shakila Meshkat, Ilya Demchenko et al.
12 citations
Ketamine may offer short-term benefits for treating substance use disorders, including alcohol, cocaine, opioid, and cannabis use disorders. In alcohol use disorder, it reduced withdrawal symptoms and the need for benzodiazepines. For cocaine use disorder, it decreased craving and increased abstinence rates. In opioid use disorder, high-dose ketamine combined with psychotherapy improved abstinence and reduced craving. For cannabis use disorder, it reduced weekly use and increased confidence in abstinence. However, the evidence is limited by small sample sizes and a lack of randomized trials. Larger, well-controlled studies are needed to determine optimal dosing, mechanisms, long-term efficacy, and risks before broader clinical use can be recommended.
Neuroscience and biobehavioral reviews
June 1, 2025
Shakila Meshkat, Gunjan Malik, Richard J Zeifman et al.
11 citations
Psilocybin-assisted psychotherapy may reduce alcohol consumption and help with smoking cessation, especially for alcohol and tobacco use disorders. In a systematic review of 16 published studies, most focused on alcohol or tobacco use, and over half used psilocybin combined with psychotherapy. Doses ranged from microdosing to 20–40 mg per 70 kg. Alcohol use disorder studies reported fewer heavy drinking days and higher abstinence rates, with brain scans showing normalized activity. Tobacco use disorder studies found high smoking abstinence rates, with mystical experiences predicting long-term success. Findings for other substance use disorders were mixed. The evidence is preliminary; larger clinical trials are needed.
Therapeutic advances in psychopharmacology
January 1, 2024
Raymond Yan, Tyler Marshall, Atul Khullar et al.
11 citations
Over a 4-week course of eight intravenous ketamine infusions, adults with treatment-resistant depression reported improved sleep quality and an earlier circadian rhythm. Sleep quality, measured by the Pittsburgh Sleep Quality Index, improved significantly, as did depressive symptoms. Circadian rhythm, measured by the Morningness-Eveningness Questionnaire, shifted earlier. Improvements in sleep duration and daytime dysfunction were also observed. The effect on sleep quality was more prominent in patients with mixed features of depression, while the circadian shift was more prominent in those without mixed features. The study was small and uncontrolled, so findings are preliminary.
Therapeutic advances in drug safety
January 1, 2025
Gilmar Gutierrez, Gustavo Vazquez, Nisha Ravindran et al.
5 citations
Intranasal esketamine, used for treatment-resistant depression, does not appear to carry significant abuse liability during an acute course of treatment. In a secondary analysis of a multicenter observational study, 23 patients with major depressive disorder reported neutral liking and no cravings for esketamine after their first dosing session, and these measures did not increase over eight sessions. Neither age, sex, baseline depression severity, side effects, nor study site influenced liking or cravings. The findings align with existing literature suggesting that acute esketamine treatment is not associated with high drug liking or cravings, though larger studies are needed.
Psychiatry and clinical psychopharmacology
August 11, 2025
Reinhard Janssen-Aguilar, Shakila Meshkat, Huda F Al-Shamali et al.
4 citations
Posttraumatic stress disorder (PTSD) is a severe condition that can be difficult to treat, prompting interest in innovative therapies. This systematic review of 94 studies evaluated interventional treatments including neuromodulation, rapid-acting pharmacotherapies like intravenous ketamine and esketamine, and psychedelic-assisted psychotherapies. Randomized controlled trials showed response rates ranging from 12.5% to 80% for transcranial magnetic stimulation, 17% to 67% for intravenous ketamine, and 50% to 87% for MDMA-assisted therapy. Most treatments were well tolerated with only mild, transient adverse effects. The review highlights variability in efficacy, safety, and tolerability across treatments, reflecting differences in patient populations, protocols, and comorbidities. While symptom improvement is observed, sustained efficacy varies, underscoring the need for maintenance strategies.
Journal of Clinical Medicine
February 20, 2025
Shakila Meshkat, Taha Malik, Jennifer Swainson et al.
3 citations
A systematic review examined whether psychedelic therapies can rapidly reduce suicide risk. Four randomized controlled trials reported significant reductions in suicidal ideation with psilocybin (three studies) and MDMA-assisted therapy (one study), with effect sizes (Cohen's d) ranging from 0.52 to 1.25 and no safety issues. Five additional randomized trials also showed reductions. Among 24 non-randomized and cross-sectional studies, results were mixed: psilocybin reduced suicidal ideation (odds ratios 0.40–0.75), MDMA-assisted therapy for PTSD showed a pooled effect of d = 0.61, while LSD was associated with increased odds of suicidality (odds ratios 1.15–2.08). DMT studies showed no significant effects. The evidence remains inconclusive, underscoring the need for further trials.
Psychiatry research
September 1, 2026
Isis Lunsky, Gilmar Gutierrez, Xena Wang et al.
Postpartum depression (PPD) is common and harmful if untreated, with few effective prevention strategies. Ketamine and esketamine are rapid-acting antidepressants showing promise for PPD. This review searched five databases for peer-reviewed randomized controlled trials, pilot studies, and observational studies examining ketamine or esketamine for PPD prevention during pregnancy or postpartum, for both cesarean and vaginal deliveries. A network meta-analysis and narrative synthesis were used. Thirty-six studies were identified; five included vaginal delivery, thirty included cesarean section, and one did not specify delivery mode. Results suggested that ketamine and esketamine were well tolerated and may reduce PPD risk. However, data quality was low to very low, so results should be interpreted cautiously. More high-quality studies are needed.
Psychopharmacology
July 1, 2026
Sarah Ann Smith, Haseeb Mohammad, Lik Hang N Lee et al.
A review of 20 studies examined whether psychedelic drugs can affect social cognition in people with psychiatric or neurodevelopmental disorders that involve cognitive impairment. The drugs studied were ketamine, MDMA, psilocybin, LSD, and ayahuasca, tested in depressive disorders, anxiety disorders, autism spectrum disorder, and post-traumatic stress disorder. Findings included neural activation patterns suggesting that ketamine and psilocybin may modulate processes relevant to social perception, especially facial emotion processing, in depressive disorders. MDMA was linked to improvements in self-reported psychosocial functioning, self-awareness, and self-compassion in participants with PTSD. Direct evidence of improved social-cognitive functioning remains limited.
Journal of Military Veteran and Family Health
February 1, 2026
Ian Stefanuk, Kaitlin Chivers-Wilson, Rakesh Jetly et al.
A retrospective chart review of 56 Veterans who completed a program combining sublingual ketamine therapy with a transdiagnostic intensive outpatient program (IOP) found significant reductions in symptoms of depression, anxiety, and posttraumatic stress, along with improved quality of life. Clinically meaningful improvements were most notable among those with moderate to severe baseline symptoms. The intervention is thought to enhance neuroplasticity and emotional learning while increasing treatment engagement and long-term resiliency. The lack of a control group limits the findings, and further research is needed to validate the results and adapt the model for Veterans.
Progress in neuro-psychopharmacology & biological psychiatry
April 2, 2025
Viktoriia Kurkova, Olga Winkler, Andrew Greenshaw et al.
A scoping review of 10 studies out of 11,734 publications examined whether psychedelic-assisted psychotherapy (PAP) can help people recover from moral injury—deep distress from morally challenging experiences. None of the studies focused specifically on moral injury; they involved psilocybin, MDMA, or LSD for conditions such as PTSD, alcohol use disorder, depression, and anxiety. Across these studies, PAP was associated with rapid, sustained increases in self-compassion, self-forgiveness, and self-acceptance, along with reduced demoralization and lower drinking scores. The authors suggest PAP holds promise for treating moral injury, especially when it co-occurs with PTSD, but conclude that direct research is needed.
Ketamine
January 1, 2025
Carson Chrenek, Jennifer Swainson
Access to effective ketamine treatments for treatment-resistant depression is limited by cost, availability, and monitoring requirements. This article synthesizes current literature on ketamine's pharmacology and describes its application in a clinical program in Edmonton, Alberta. Topics include the rationale for maintenance treatments, monitoring long-term safety, and alternative options such as sublingual or at-home ketamine to improve patient access. The authors review considerations for cautious prescribing outside highly monitored settings.
Journal of Clinical Psychopharmacology
August 1, 2018
Shaina Archer, Carson Chrenek, Jennifer Swainson
In a small group of 11 patients with treatment-resistant depression who initially responded to an acute course of ketamine infusions, ongoing maintenance infusions helped sustain the antidepressant effect for some. All patients had lower depression scores during maintenance treatment than at baseline. At the end of the observation period, 4 patients continued maintenance ketamine, 1 switched to intranasal ketamine, 4 stopped because the drug lost its effect, 1 stopped due to side effects, and for 2 the reason was unrecorded. No major adverse events occurred, and the treatment was generally well tolerated. The authors suggest maintenance ketamine may help some responders, but more research is needed on optimal duration and long-term safety.