Oral ketamine for the treatment of pain and treatment-resistant depression

Schoevers and colleagues frame the review around the discovery that ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects when given intravenously. Earlier clinical trials and open-label reports in treatment-resistant unipolar and bipolar depression found symptom reductions within hours to days after a 0.5 mg/kg i.v. infusion, implicating glutamatergic modulation and downstream synaptic plasticity as mechanisms distinct from traditional monoaminergic antidepressants. However, the antidepressant effect of single i.v. doses is typically short-lived, and efforts to prolong benefit (for example, by repeated infusions or adjunctive agents) have had mixed results. The pain-management literature, by contrast, includes more experience with non-intravenous routes and longer treatment durations, suggesting that insights from chronic pain practice could inform psychiatric applications. This paper sets out to review the clinical literature on ketamine across routes of administration, with particular focus on oral ketamine: dosing regimens, duration of treatment, effects and adverse events for treatment-resistant depression and for chronic pain. The authors aim to bring together evidence from both fields to evaluate whether oral (and other non-intravenous) ketamine might offer a tolerable maintenance strategy for depression and what safety, pharmacokinetic and methodological gaps remain.

The study is a narrative literature review built from systematic searches of PubMed using combinations of terms for ketamine and indications (oral, intravenous, intranasal, subcutaneous ketamine crossed with depression, chronic pain or neuropathic pain). The final search date reported was 27 October 2014. From an initial set of 112 records the authors excluded reviews, animal studies and studies in healthy volunteers, yielding 88 studies for data extraction. Extracted items included study type and size, dosing regimen, number of individuals exposed to ketamine, number of ketamine days per study, outcomes and adverse events. Results were tabulated and used to create summary graphs (tables and figures are referred to as available online). Rather than performing a quantitative meta-analysis, the review used descriptive synthesis and standardised dose comparisons by converting reported doses to a daily oral racemate equivalent (mg/kg/day). To do this the authors applied bioavailability correction factors: intravenous doses were multiplied by five to reflect lower oral bioavailability on average; (S)-ketamine doses were multiplied by two to account for greater potency; intranasal, intramuscular and sublingual doses were adjusted by reported conversion factors (2.25, 4.65 and 1.5 respectively). The review reports counts of studies by route and indication (for example, the extracted text states totals for depression and pain by route), but the extraction contains some inconsistencies about the exact number of oral depression studies; where counts appear discrepant between sections the extracted text does not clearly reconcile them.

Oral ketamine for depression: The extracted text describes only small, uncontrolled studies of oral and sublingual ketamine for treatment-resistant depression. Across the reports, doses and schedules varied: one very small study (n = 4) used up to 1.25 mg/kg oral (S)-ketamine for 2 weeks with reported benefit; hospice case reports described daily 40 mg oral ketamine relieving pain, anxiety and depressive symptoms, and single 0.5 mg/kg oral doses producing brief improvements in two severely ill patients. A hospice-based 28-day open trial of daily 0.5 mg/kg reportedly had 8 of 14 completers with significant improvements in pain and depression. De Gioannis & De Leo treated two patients with chronic suicidal ideation with orally ingested ketamine up to 3 mg/kg and reported sustained remission of suicidal thoughts. A sublingual regimen reported by Lara et al (10 mg administered at intervals up to a total of 20 doses) found mood improvements in 20 of 26 patients. The authors emphasise that these studies are small, uncontrolled and of low methodological quality, so the data only provide preliminary indications of possible antidepressant effects. Dosing regimens and duration for pain versus depression: When doses are expressed as daily oral racemate equivalents, the review finds antidepressant studies generally used lower doses and much shorter treatment durations (commonly 1–32 days) than analgesic studies. Pain studies employing oral ketamine ranged from single doses to continuous use lasting up to 660 days, with most in the 20–80 day range. Reported bioavailability for oral ketamine in adults was typically 17–24%, with larger and more variable values reported under special conditions (for example, up to 45% in a paediatric nasogastric study). Intranasal bioavailability figures of about 30–45% and intramuscular bioavailability around 93% are also cited. The authors note wide interindividual variability in oral absorption related to formulation, gastric factors and metabolic phenotype. Although the heterogeneous data preclude firm dose–response conclusions, most pain studies reported pain reduction even at relatively low oral doses, while a minority of intravenous studies failed to reduce pain; one high-dose study (Kapural et al, reported equivalent 21.5 mg/kg/day) did not improve long-term pain in patients with high opioid requirements. Safety and abuse potential: Across routes, psychotomimetic and dissociative effects are most prominent with i.v. administration and correlate with high peak plasma concentrations; these acute psychedelic effects are described as usually resolving within about 2 hours after i.v. infusion. Oral administration appears to produce fewer or milder acute psychedelic effects in the studies reviewed. Frequently reported adverse events for oral ketamine included dizziness/light-headedness, nausea, vomiting, drowsiness, confusion, headache, somnolence and disturbing dreams; hallucinations and paranoid feelings were rare. Very-low-dose sublingual administration (10 mg) was not associated with euphoria or psychotic/dissociative symptoms. Preclinical neurotoxicity findings are discussed (including concerns about apoptosis in primate studies), but human clinical series with limited or intermittent dosing generally did not report persistent cognitive deficits. Heavy recreational misuse has been associated with white-matter changes, memory and cognitive impairments and severe urological damage; the review notes these users consumed daily amounts far exceeding therapeutic doses (calculated examples imply roughly 80 mg/kg/day oral racemate equivalent in heavy users, substantially higher than clinical protocols). The authors report that addiction or misuse was not documented as a major problem in the reviewed pain and depression studies, but they stress the potential for misuse especially with rapid-onset routes such as i.v. or inhalation.

Schoevers and colleagues conclude that oral ketamine, at the doses and schedules described in the reviewed literature, appears to be reasonably well tolerated, but that there is a paucity of systematic data on longer-term harms and sustained efficacy. They highlight that depression studies tend to be short in duration relative to pain studies, and that knowledge from chronic pain management—where oral ketamine has been used for longer periods—could inform psychiatric research. The authors identify several priorities for future work: basic-science studies to clarify mechanisms, acceptability and feasibility work, ethical analyses, and, importantly, rigorous randomised controlled trials of oral ketamine given for weeks rather than days in treatment-resistant depression. Key concerns the authors discuss include the potential for misuse, which would require monitoring if ketamine were to be scaled clinically, and a cautious stance on broader, unsupervised use. They recommend that initial administration occur in a hospital setting with consideration of outpatient maintenance only after individual risk assessment, and that side-effects be systematically monitored with standard instruments. Pharmacokinetic variability and low oral bioavailability argue for measurement of blood levels and attention to formulation in future studies. Finally, because ketamine's antidepressant effects may overlap mechanistically with analgesia in patients who also have pain, upcoming trials should assess both depressive and pain outcomes. Overall, the authors advocate for carefully designed RCTs to establish the balance of benefit and potential adverse consequences of longer-term oral ketamine for treatment-resistant depression.