Ketamine-assisted psychotherapy treatment of chronic pain and comorbid depression: a pilot study of two approaches

Araya and colleagues frame the study within rising rates of both major depressive disorder (MDD) and chronic pain in the US, and the limited effectiveness of standard pharmacological and psychotherapeutic approaches for many patients. They note ketamine's multiple putative mechanisms—NMDA antagonism leading to enhanced glutamatergic/AMPA signalling and synaptogenesis, anti-inflammatory effects, modulation of cortical dynamics and dopamine availability, and distinct subjective psychological effects including altered states and trauma processing—and argue these mechanisms may be relevant to both depression and centrally sensitised pain. The authors highlight several gaps in the literature: uncertainty about optimal route of administration (beyond IV data), uncertainty about whether higher doses that produce altered states are necessary for therapeutic benefit, limited study of ketamine paired with psychotherapy, and scarce data on ketamine for co-occurring chronic pain and depression. This pilot study therefore set out to examine two clinical KAPT (ketamine-assisted psychotherapy) approaches in patients with comorbid MDD and a chronic pain disorder. Specifically, the investigators compared a ‘‘psychedelic’’ model (higher intramuscular doses given 24 hours before therapy) with a ‘‘psycholytic’’ model (lower oral/sublingual doses administered during therapy), asking whether route and dose (and the altered states they produce) differentially affect depressive, pain, anxiety, and PTSD symptoms. The authors present this as an initial, observational contribution intended to guide larger, controlled studies.

This was a small, observational single-subject design with repeated measures. Ten adult participants (N = 10) with prior diagnoses of MDD and a comorbid chronic pain condition were recruited from two clinical sites using flyers and online outreach; the extracted text does not report additional inclusion/exclusion criteria in full. Participants completed baseline questionnaires (T0) and repeated outcome assessments after the first (T-1), third (T-2) and sixth/final (T-3) ketamine sessions. Allocation to treatment was non-random and determined by the treating clinicians based on weight, previous psychedelic use, participants' anxiety about non-ordinary states of consciousness and treatment intentions; five participants received the psychedelic protocol and five the psycholytic protocol. The psychedelic protocol comprised intramuscular (IM) ketamine injections across six weekly sessions, two IM injections per session with session-by-session dose escalation; reported per-session IM ranges were 40–100 mg overall (standard regimen listed as 40/50 mg in session 1 up to 90/100 mg in session 6). The psycholytic protocol comprised oral/sublingual ketamine lozenges across six weekly sessions, with doses escalating from 25 mg (sessions 1–2) to 50 mg (3–4) to 75 mg (5–6); participants were instructed to hold and swish the lozenge for about 15 minutes to maximise mucosal absorption and to participate in therapy during drug administration. All participants received preparatory and integration psychotherapy from a trained integrative mental health clinician; the therapy included intake review of trauma and developmental history, goal-setting, provision of a workbook, and six therapy sessions using eye movement desensitisation and reprocessing (EMDR), mindfulness and self-regulation skills. For the psychedelic group, therapy sessions took place about 24 hours after IM dosing; for the psycholytic group, therapy occurred while the sublingual dose was active. Outcome measures included the Beck Depression Inventory (BDI), the Brief Pain Inventory (BPI) Short Form (pain severity and interference), the Generalized Anxiety Disorder Scale (GAD-7), the PTSD Checklist (PCL-5), and the Mystical Experience Questionnaire (MEQ30). The authors describe participants as their own controls, comparing T-1 to T-3 against baseline T0, and they also compared mean outcomes between the two treatment groups at each timepoint. A chi-squared test was reported for comparisons of mean outcome scores at T-1 to T-3 between groups; the study also reports percent changes and p-values for group comparisons. Treatments were delivered at named clinic locations and outcome data were collected via REDCap. Safety/tolerability was monitored and no drug-related serious adverse events were reported.

Overall, all ten participants improved across the measured domains by study end, but no between-group differences reached statistical significance, which the authors attribute to limited sample size and statistical power. Mystical experiences (MEQ30): Mean MEQ30 scores were higher in the psychedelic group at all timepoints, but differences were not statistically significant (T-1 p = .46; T-2 p = .46; T-3 p = not clearly reported). The extracted text gives absolute mean differences favouring the psychedelic group of 22.8 points at T-1, 25.6 points at T-2 and 33.4 points at T-3. Pain (BPI): The groups did not differ significantly on pain interference at any timepoint (T-1 p = .90; T-2 p = .22; T-3 p = .96). Descriptively, the psychedelic group had a larger mean reduction in pain interference (36.36% decrease from baseline to T-3) than the psycholytic group (8.9% decrease). The psychedelic group showed a generally steady decline across sessions with a small blip after session 3, whereas the psycholytic group's pain interference fluctuated (increase between T0 and T-1, decrease between T-1 and T-2, then increase between T-2 and T-3). Depression (BDI): Mean BDI scores fell in both groups. The psychedelic group mean BDI decreased from 42 at baseline to 36.8 at T-3; the psycholytic group decreased from 44.6 to 38.4. The authors report no statistically significant differences between groups at T-1 (p = .83), T-2 (p = .79) or T-3 (p = .79). Temporal patterns differed: after session 1 the psychedelic group's mean BDI increased by 4.12% while the psycholytic group's decreased by 7.17%; both groups showed ≈10% mean decreases by session 3; between T-2 and T-3 the psychedelic group continued to fall by a further mean 6.60% while the psycholytic group increased by a mean 3.70%. Anxiety (GAD-7): No statistically significant between-group differences were found (T-1 p = .59; T-2 p = .97; T-3 p = .72). All participants moved from mean scores in the severe range at baseline to mean scores in the moderate range by T-3. The psychedelic group showed a larger overall mean reduction (19.57%) than the psycholytic group (16.25%). Group trajectories differed: the psychedelic group's mean anxiety decreased consistently, while the psycholytic group showed an increase after session 3 before decreasing again by T-3. PTSD (PCL-5): The extracted text reports that baseline PCL-5 scores were uniformly high (all ≥50) and that scores declined in both groups by T-3. The authors state that the psychedelic group experienced a clinically significant mean decrease in PTSD severity, whereas the psycholytic group's decrease was described as reliable but not clinically significant; exact mean PCL-5 values and p-values are not provided in the extracted text. Safety: Both approaches were reported as well tolerated with no drug-related serious adverse events and no clinically significant vital sign abnormalities observed.

Araya and colleagues interpret their findings as preliminary support that ketamine-assisted psychotherapy can reduce depressive, pain, anxiety and PTSD symptoms in patients with comorbid MDD and chronic pain. They emphasise that participants receiving the higher-dose intramuscular ‘‘psychedelic’’ protocol experienced larger and more consistent improvements and greater altered states of consciousness as measured by the MEQ30, although no between-group differences were statistically significant. The authors position these outcomes in line with prior work suggesting that ketamine has both neurobiological and psychological mechanisms; they argue their data are compatible with the hypothesis that greater consciousness alteration may mediate stronger clinical responses. They also link reductions in PTSD and improvements across domains to a possible role of trauma in the aetiology and maintenance of some chronic pain conditions, noting that all participants had high baseline PTSD symptom burden which declined alongside pain and mood symptoms. Key limitations acknowledged by the authors include the very small sample size, non-randomised allocation and the observational design, which prevent causal inference and allow for selection bias because clinicians chose the treatment approach for each patient. The design also conflated dose and route of administration, so the relative contribution of dose versus route remains unresolved. The absence of a control group means improvements could reflect therapy alone, nonspecific effects, or natural history rather than ketamine per se. The authors further note that follow-up was limited to the end of treatment, so durability of effects is unknown. For future research the authors call for larger, randomised and controlled trials that separate dose from route, include control arms (for example ketamine alone, therapy alone, and combined KAPT), incorporate longer-term follow-up, and add qualitative methods to capture patient experience. They also suggest further study of KAPT for GAD and PTSD, and investigation into the role of trauma in chronic pain and depression.

The authors conclude that ketamine-assisted psychotherapy showed promise as a treatment for individuals with comorbid chronic pain and major depressive disorder, and that improvements were also observed in anxiety and PTSD symptoms. Findings from this small pilot indicate the intramuscular, higher-dose ‘‘psychedelic’’ approach produced larger and more consistent symptom reductions than the low-dose oral/sublingual ‘‘psycholytic’’ approach, but the absence of statistical significance and the study's methodological limitations prevent definitive claims. Araya and colleagues recommend larger, randomised, controlled and longer-term studies that disentangle dose and route effects, include qualitative investigation of patient experience, and evaluate durability of benefit to inform clinical implementation.