Oral Ketamine for Depression: An Updated Systematic Review

Major depressive disorder (MDD) and bipolar depression impose a substantial global burden, causing impairment across social and occupational functioning, increased mortality, and economic costs. Current antidepressant treatments are effective only in a subset of patients, with over 30% failing to respond to standard therapies and many agents exhibiting delayed onset of action that can increase suicide risk. Ketamine, an N-methyl-D-aspartate receptor antagonist originally used as an anaesthetic, has emerged as a rapid-acting antidepressant with demonstrated anti‑suicidal effects in intravenous (IV) trials. Oral formulations are of particular interest because they are more accessible and scalable than IV administration, and several small studies have examined oral ketamine, esketamine and r‑ketamine for unipolar and bipolar depression. Meshkat and colleagues undertook an updated systematic review to synthesise evidence on the efficacy, tolerability and safety of oral and sublingual ketamine formulations for depressive disorders. The review aimed to capture studies published up to September 2022 and to clarify dose ranges, administration schedules, and reported antisuicidal effects, with particular attention to treatment‑resistant depression (TRD). The authors framed the work as an update to earlier reviews in light of an expanding literature since 2019.

The investigators conducted a systematic literature search of PubMed, Scopus, Google Scholar and selected reference lists from January 2019 to September 2022, and incorporated eligible studies identified in their prior review (covering records before January 2019) to produce a comprehensive update. Search terms combined administration routes ((oral OR sublingual OR PO OR SL OR transmucosal)), diagnostic terms (depression OR MDD OR bipolar), and ketamine variants (ketamine OR esketamine OR r‑ketamine). The authors included both new and previously identified studies. Eligibility followed a PICO framework: population—patients with unipolar or bipolar depression; intervention—oral or sublingual ketamine (including S‑ or R‑enantiomers); outcome—measures of depressive symptom severity. Human studies in English were eligible, and study designs accepted ranged widely (randomised and non‑randomised trials, open‑label studies, case series, case reports, and retrospective chart reviews). Exclusions were animal studies, systematic reviews/meta‑analyses, letters, and studies using non‑oral routes. Two reviewers extracted standardised data items from each included article: author/year, design, participants, outcomes and measures, inclusion criteria, concomitant treatments, interventions, findings, limitations, adverse events, antisuicidal effects, and indications of efficacy in TRD. Suicidality was judged to have declined if authors reported fewer suicide attempts, reduced suicidal ideation, or lower scores on suicide rating scales. The review team considered evidence of efficacy in TRD present when studies demonstrated benefit in participants who had failed two or more adequate prior treatments. Risk of bias for randomised trials was assessed using domains from the Cochrane Handbook, specifically random sequence generation, allocation concealment, blinding of participants, incomplete outcome data, and selective reporting. The authors note a study selection flow (initial 210 records, 22 final included studies) and present characteristics in tabular form (figures/tables referenced in the extracted text).

The search process yielded 210 records; after removing 32 duplicates and screening titles/abstracts, 28 full texts were reviewed and 22 studies met inclusion criteria. Those 22 studies comprised four randomised clinical trials (RCTs), five open‑label trials, six retrospective chart reviews, one case series and six case reports, encompassing a total of 2336 patients with depressive disorders. Across study types, dosing and schedules were heterogeneous. Reported oral ketamine doses ranged from about 0.25 mg/kg to 1.5 mg/kg in retrospective and real‑world studies, with several trials using 0.5–1.25 mg/kg; administration frequency varied from daily to monthly, and some programmes delivered outpatient or virtually monitored at‑home dosing. The authors state that all included studies reported statistically significant improvements in depressive symptoms following oral ketamine, and ketamine was generally described as well tolerated without serious adverse events in the included reports. RCT findings: Domany et al. conducted a 21‑day, double‑blind, placebo‑controlled outpatient trial in treatment‑resistant depression, administering 1 mg/kg oral ketamine three times daily for three weeks (22 on ketamine, 18 placebo). The ketamine group showed significant reductions in MADRS scores at all post‑baseline time points (p < 0.005), and responder rates at day 21 were higher in the ketamine arm (seven responders, 31.8%) versus placebo (one responder, 5.6%; p < 0.05). Arabzadeh et al. evaluated adjunctive oral ketamine (50 mg/day) added to sertraline 150 mg/day in moderate–severe MDD and found greater HDRS improvements at weeks 2, 4 and 6 (p = 0.001, 0.001 and 0.009 respectively). Jafarinia et al. compared daily oral ketamine (150 mg) with diclofenac (150 mg) over six weeks; no between‑group HDRS difference was seen at week 3, but at week 6 HDRS reduction favoured ketamine (p = 0.017), and HADS depression subscale reductions were significantly greater for ketamine at weeks 2 and 6 (p = 0.012). A small pilot study randomising patients to intramuscular ketamine, oral R‑ketamine (1 mg/kg every 2–3 days), or electroconvulsive therapy reported significant HDRS and suicidal ideation score reductions across all three arms with no significant differences between groups (p < 0.001). Open‑label and real‑world studies: Five open‑label trials included a range of populations and dosing regimens. One open‑label study in 32 patients with chronic suicidality used weekly oral ketamine over six weeks with flexible titration up to 3.0 mg/kg; Beck Scale for Suicide Ideation scores fell significantly at follow‑up versus baseline (p < 0.001), and MADRS decreased from 38.6 to 15.9 (p < 0.05). A large telehealth ketamine‑assisted therapy programme reported outcomes in 1247 outpatients given a single 300–450 mg sublingual tablet to establish dosing; 62.8% and 62.9% of patients reported ≥50% improvements on the PHQ‑9 and GAD‑7 respectively, with remission rates of 32.6% (PHQ‑9) and 31.3% (GAD‑7). Smaller open‑label trials included a multiple‑dose flexible regimen in seven TRD patients (MADRS mean 5.7 at 96 hours), a 28‑day daily 0.5 mg/kg regimen in eight participants (all 100% had ≥30% HADS reductions), and a three‑week low‑dose repeated oral esketamine series in TRD patients showing a modest mean HRSD fall from 23.6 to 19.7 (16.5%), with variable follow‑up trajectories. Retrospective and case literature: Thirteen retrospective and case studies (total n = 813) predominantly involved TRD or unipolar depression and reported consistent symptom reductions with oral ketamine, doses between 0.25 and 1.5 mg/kg, and generally tolerable adverse event profiles. Two of these reports documented anti‑suicidal effects. The authors note heterogeneity across protocols and dosing. Risk of bias: the RCTs were judged to have high risk of bias in parts due to analytic methods and adverse event monitoring. The paper also notes an inconsistency in the extracted text regarding the number of RCTs considered for meta‑analysis; the authors conclude that a meta‑analysis was not feasible because of wide heterogeneity in designs and dosing.

Meshkat and colleagues interpret the aggregated literature as preliminary but consistent evidence that oral ketamine is associated with clinically meaningful reductions in depressive symptoms and, in several studies, reductions in suicidal ideation. They emphasise that findings are more optimistic compared with their prior review, reflecting an increase in published studies and registered clinical trials, including outpatient programmes with virtually monitored home dosing. The authors discuss practical advantages of oral administration—improved feasibility, lower costs and greater patient convenience relative to IV infusions—and note that oral ketamine has an extensive history of at‑home use for chronic pain. Nonetheless, they caution that outpatient or at‑home ketamine raises safety considerations: ketamine is psychotomimetic, its safety in psychotic disorders is uncertain (such patients were excluded from outpatient studies), and risks include impaired driving, dependence potential, and management of acute side effects such as nausea, hypertension and anxiety. Pharmacokinetic and safety considerations are addressed: oral ketamine undergoes substantial first‑pass metabolism (mainly to norketamine via CYP3A4), yielding lower and more variable bioavailability (reported around 10–20%) which may reduce some adverse events compared with IV or intranasal routes. The authors contrast oral bioavailability with intranasal administration (25–50% reported) and note that intranasal formulations have gained regulatory approval when combined with oral antidepressants for TRD. Key limitations acknowledged by the authors include the small number of large, high‑quality, replicated RCTs; small sample sizes, variable and often short follow‑up durations; and wide heterogeneity in dosing regimens, formulations and monitoring approaches. The review notes a potential for relapse after cessation of treatment (citing relapse estimates after esketamine) and flags cognitive risks with long‑term, high‑dose use. On balance, the authors call for larger Phase III RCTs and longer follow‑up to define optimal dosing, frequency, monitoring requirements (including supervised versus virtual at‑home administration) and to better characterise antisuicidal effects and safety with prolonged use.

The review concludes that preliminary clinical trials and larger real‑world datasets offer supportive evidence for antidepressant effects of oral ketamine, but emphasises that further research is required. Specifically, the authors recommend large, well‑designed Phase III randomised trials to compare oral ketamine with other routes (IV, IM, intranasal) and standard treatments, and to optimise protocols for dose, frequency and monitoring (including at‑home virtual monitoring versus in‑clinic supervision).