Safety, effectiveness and tolerability of sublingual ketamine in depression and anxiety: A retrospective study of off-label, at-home use

Major depressive disorder (MDD) is highly prevalent and frequently resistant to first-line treatments: roughly half of patients respond to standard antidepressants and about 30% meet criteria for treatment‑resistant depression (TRD). Comorbid anxiety—particularly generalized anxiety disorder (GAD)—is common in people with TRD, worsens course and treatment outcomes, and complicates pharmacological strategies (for example, benzodiazepine use may attenuate ketamine’s antidepressant effects). Intravenous (IV) ketamine and intranasal (IN) esketamine have attracted clinical attention and regulatory approval for TRD, but IV approaches require medicalised settings and carry cost and access barriers. Hartelius and colleagues situate sublingual (SL) rapid‑dissolve ketamine tablets (RDT) as a pragmatic alternate delivery route with higher transmucosal bioavailability than oral dosing (approximately 30% vs 10–20%). Responding to COVID‑19–era constraints, the investigators conducted a retrospective chart review of an at‑home, clinician‑supervised SL ketamine programme to assess safety, tolerability and change in depressive and anxiety symptoms after three and six self‑administered RDT doses (300–450 mg). The study aims to evaluate whether SL ketamine delivered at home is a viable option for patients with TRD and treatment‑resistant anxiety and to extend prior prospective work in this area.

Ethical approval for this retrospective review was granted by the Wheaton College Institutional Review Board (Protocol #1828103-1; Exempt Category 4.iii), approved 11/15/2021. Data were drawn from a telemedicine practice offering at‑home SL ketamine (My Ketamine Home) between (as reported in the extracted text) 12/1/2020 and 9/30/2021. Patients completed an online registration and a telemedicine intake consultation with Psychiatric Mental Health Nurse Practitioners who applied DSM‑5 criteria to diagnose MDD and GAD. Baseline measures included the Patient Health Questionnaire (PHQ‑9) and the Generalized Anxiety Disorder Screener (GAD‑7). Clinically relevant medical history and prior treatment failures were recorded as part of the intake. Exclusion criteria, as reported, comprised active suicidal ideation, uncontrolled hypertension (systolic ≥140 mmHg or diastolic ≥90 mmHg, based on self‑reported screening), liver disease (based on available liver function tests and history), schizophrenia or other primary psychotic disorders, and active substance use disorder. Prescription monitoring checks were used to assess potential diversion risk. After informed consent, patients were mailed an initial shipment containing a single 300 mg ketamine RDT and detailed safety and set/setting instructions. Patients were advised to have a sober sitter present, avoid other psychoactive substances (including alcohol and cannabis), and refrain from benzodiazepines on the day of ketamine due to potential interaction with antidepressant effects. The intended treatment schedule mirrored IV ketamine protocols: self‑administration twice weekly. After the first RDT and an online experience report, clinicians could approve a second shipment of two additional RDTs (300 mg or increased to 450 mg based on reported tolerability), yielding three total doses (3‑RDT). Following review of the second experience report, clinicians could authorise a final shipment of three further RDTs to complete a six‑dose course (6‑RDT). Outcome measures were changes in PHQ‑9 and GAD‑7 scores from intake to post‑3‑RDT and post‑6‑RDT, and self‑reported side effects rated as None, Mild, Moderate or Severe (including nausea, dizziness, headache, loss of balance, among others). Statistical analyses used SPSS v28. Wilcoxon matched‑pairs tests assessed pre‑to‑post changes in GAD‑7 and PHQ‑9 scores at the 3‑ and 6‑dose timepoints. The investigators also reported the proportion of patients achieving ≥50% raw score reductions and the proportion whose intake scores in the Moderate–Severe range moved into None–Mild categories. The extracted text provides several sample counts but contains some inconsistencies: the dataset screening reportedly considered 4,404 people with 1,101 enrolled; 669 patients were said to have completed at least three RDTs, five of whom were excluded for corrupted data, leaving 664 for analysis in one statement, while some inferential results cite different Ns (see Results). The study therefore analysed all patients who completed follow‑up surveys after at least 3‑RDT, with a subgroup analysis of those who completed 6‑RDT.

Sample and data completeness: As extracted, 4,404 people were assessed for eligibility and 1,101 patients enrolled in the telemedicine programme. The authors report 669 patients completed at least three SL ketamine RDT and submitted post‑treatment reports; five records were excluded for missing/corrupted data, leaving 664 for PHQ‑9 and GAD‑7 analyses in one account. A subgroup of 210 patients reportedly completed the six‑dose course and corresponding follow‑up. The extracted text also contains differing Ns in specific analyses (for example, a Wilcoxon analysis cited n = 654); the text does not consistently reconcile these discrepancies. Safety and tolerability: Follow‑up procedures systematically screened for major adverse events requiring medical care, and side effects were collected by self‑report. Reported adverse effects included nausea, dizziness, headache and loss of balance; these effects were described as self‑limited and resolving without further medical intervention in the extracted text. The manuscript does not clearly report any hospitalisations or other major adverse events in the provided text. Impact after three RDT doses: Wilcoxon matched‑pairs tests showed statistically significant reductions in both anxiety and depression after three RDTs. For GAD‑7 (analysis reported with n = 654), the decrease from intake was significant (z = -18.52, p < 0.001) with an average raw reduction of 4.86 points. Overall, 47.6% of patients (n = 316) achieved ≥50% reduction in GAD‑7 scores from intake. Among those with intake GAD‑7 in the Moderate–Severe range (GAD‑7 ≥ 10; n = 418 as reported), 47.6% (n = 199) had ≥50% reductions and 63% moved into None (0–4) or Mild (5–9) anxiety categories after three doses; a substantial minority did not show clinical reduction. For PHQ‑9, three RDTs produced a significant reduction (z = -19.71, p < 0.001) and an overall mean reduction of 47.59% from intake. In the Moderate–Severe intake PHQ‑9 subgroup (n = 463), 49.5% (n = 229) achieved ≥50% reductions and 59% (n = 273) reported clinically significant drops into None–Mild depression categories; 41% did not experience a clinical reduction after three doses. Impact after six RDT doses: Among patients who completed the six‑dose course (n = 210 as reported), further improvement was observed. GAD‑7 scores decreased significantly from intake after the initial three doses (z = -10.12, p < 0.001) and showed an additional significant decrease after the subsequent three doses (z = -4.62, p < 0.001). Mean raw GAD‑7 reduction after six doses was 5.88 points, and 72.4% (n = 152) of the 6‑RDT group achieved ≥50% reductions from intake. In the Moderate–Severe GAD‑7 intake subgroup for the 6‑RDT sample (n = 133), 60.2% (n = 80) had ≥50% reductions and 69.2% (n = 92) shifted to None–Mild anxiety; 30.8% did not experience a clinical reduction. PHQ‑9 analysis in the 6‑RDT group also showed significant reductions: a significant change after three doses (z = 10.96, p < 0.001) and further reduction after six doses (z = 4.45, p < 0.001). For those with Moderate–Severe baseline PHQ‑9 (n = 156), six doses led to ≥50% reductions in 65.4% (n = 102) and clinically significant drops to None–Mild in 71.2% (n = 111). A figure (referenced in the text) reportedly compares mean GAD‑7 and PHQ‑9 scores at baseline, after 3‑RDT and after 6‑RDT for the 3‑ and 6‑dose groups.

Hartelius and colleagues interpret their findings as supporting the safety and clinical effectiveness of at‑home SL ketamine RDT for reducing depressive and anxiety symptoms in a treatment‑resistant population. The investigators highlight that nearly half of patients with Moderate–Severe depression achieved a ≥50% reduction in PHQ‑9 and GAD‑7 after three at‑home doses, with higher response rates (around 60–72%) among those completing a six‑dose course. They suggest that at‑home SL administration may offer an accessible alternative to clinic‑based IV infusions and note the pharmacological implication that ketamine’s mechanism (involving glutamatergic systems) could address depressive presentations not responsive to monoaminergic antidepressants. The authors acknowledge several key limitations: the retrospective design, a self‑selecting convenience sample, reliance on self‑report measures, and the absence of a placebo or control group—important given ketamine’s dissociative effects that can potentiate placebo response. They also note uncertainty about the durability of response and whether the number of treatments affects maintenance of benefit. Clinical cautions are emphasised for patients with suicidality, uncontrolled hypertension, liver disease or substance misuse, consistent with the study’s exclusion criteria. In terms of future directions, the paper calls for randomised trials, longer‑term follow up to evaluate remission durability, investigation of optimal dosing regimens and predictors of response, combinations with psychosocial interventions, broader functional outcomes and cost‑effectiveness analyses. Despite limitations, the investigators conclude that at‑home SL ketamine RDT appears to be a promising, tolerable option warranting further controlled study.