Single versus repeated sessions of ketamine-assisted psychotherapy for people with heroin dependence

Earlier research on psychedelic-assisted psychotherapy suggested that a single high-dose session can produce pronounced short-term therapeutic effects that often attenuate after a few weeks, a phenomenon described as the ‘‘psychedelic afterglow’’. Ketamine, an NMDA receptor antagonist used at sub‑anaesthetic doses, produces intense, sometimes transformative experiences that share features with near‑death phenomena and have been reported to prompt insights, shifts in life meaning and motivation that may support abstinence from substances. Prior single‑session ketamine‑psychotherapy (KPT) studies in people with alcohol and heroin dependence indicated clinical benefit, but did not address whether repeating sessions could extend or stabilise those benefits. Krupitsky and colleagues set out to compare the efficacy of a single KPT session versus a multiple‑session KPT regime (three sessions total, spaced one month apart) for promoting abstinence in people with heroin dependence. The study aimed to test whether administering additional monthly KPT sessions, with preparatory and integration counselling, would increase one‑year abstinence rates relative to a single inpatient KPT session followed by counselling only.

This was a randomised clinical study conducted after inpatient detoxification. Fifty‑nine heroin‑dependent inpatients who met the inclusion and exclusion criteria were enrolled and all received an initial KPT session while still hospitalised. Randomisation into treatment arms occurred after that first KPT session but before any subsequent sessions or counselling. Participants were then allocated to either a multiple KPT group (two additional monthly KPT sessions plus counselling) or a single KPT group (no further KPT, only counselling at monthly intervals). Key procedural elements included intramuscular ketamine at 2.0 mg/kg administered during each KPT session, a psychotherapeutic setting with eye shades and music, and existentially oriented psychotherapy focused on meaning and motivation for sobriety. Before the first ketamine session participants received five hours of preparatory psychotherapy and five hours of post‑session integration psychotherapy; before the second and third KPT sessions the multiple‑KPT group received one hour of counselling to prepare and one hour thereafter to integrate the experience. An anaesthesiologist was present for all KPT sessions. Clinical evaluators who performed psychological and clinical assessments during treatment and follow‑up were blind to group assignment. Eligibility criteria required current heroin dependence for at least one year, age 18–35, at least high school education, at least two weeks' abstinence from heroin and other substances, no psychotropic medication, and the availability of a relative to assist with follow‑up, among other practical requirements. Exclusion criteria included major psychiatric disorders (organic, schizophrenia, major affective disorder), seizure disorder, alcoholism or polydrug dependency, significant medical disease, pregnancy, and other conditions that would contraindicate participation. Outcomes and follow‑up procedures were structured around abstinence as the primary outcome, determined by monthly follow‑up interviews, physical examination for injection marks, urine toxicology and collateral reports from relatives over 12 months. Secondary outcomes comprised psychometric measures administered before and after sessions and at follow‑up: Zung Self‑Rated Depression Scale (ZDS), Spielberger State‑Trait Anxiety Scale (SAS), a Visual Analog Scale of Craving for Heroin (VASC), and the Purpose‑in‑Life Test (PLT). Statistical analysis used SPSS 11.0; survival analysis (Kaplan‑Meier) assessed differences in abstinence over time, and repeated‑measures MANOVA with post‑hoc Tukey tests analysed psychometric changes.

Of 73 patients screened, 59 met entry criteria (mean age 22.6 ± 3.9 years; mean heroin use duration 38.8 ± 30.4 months; 49 males, 10 females) and received the initial KPT session. Six participants relapsed and dropped out within the first month after that initial session, before randomisation. The remaining 53 participants were randomised: 26 to the multiple KPT group and 27 to the single KPT group. Baseline characteristics (age, duration of heroin use, gender) did not differ significantly between groups. During the treatment phase, four of 26 participants in the multiple KPT group (15.4%) relapsed after the second session but before the third, while seven of 27 in the single KPT group (25.9%) relapsed after the first counselling session; the difference in retention during treatment was not statistically significant. Kaplan‑Meier survival analysis over the 12‑month follow‑up showed a significantly higher abstinence rate in the multiple KPT group throughout the year. At one year, 13 of 26 participants (50%) in the multiple KPT group remained abstinent compared with 6 of 27 participants (22.2%) in the single KPT group (p < 0.05). The authors also note that if the six participants who relapsed prior to randomisation are counted with the single‑KPT cohort, the single‑session abstinence rate at 12 months would fall to 18.2%. On psychometric secondary outcomes, depression, state and trait anxiety, and heroin craving were significantly reduced after the first KPT session in both groups and continued to decrease in participants who remained in follow‑up; there were no significant differences between single and multiple KPT groups on ZDS, SAS, VASC or PLT scores. Purpose‑in‑Life (PLT) scores improved similarly in both groups. Safety findings reported no cases of protracted psychosis, flashbacks, or ketamine addiction; the only noted adverse effect was an acute increase in blood pressure (particularly diastolic) of about 20%–30% during KPT sessions.

Krupitsky and colleagues interpret their findings as evidence that a program of three KPT sessions spaced monthly is more effective at promoting one‑year abstinence from heroin than a single KPT session followed by counselling. The multiple‑session group had an abstinence rate more than twice that of the single‑session group at 12 months (50% versus 22.2%), and Kaplan‑Meier analysis indicated this advantage persisted across the year. The authors relate these results to historical observations with other psychedelic therapies in which single‑dose benefits tended to fade, proposing that repeated sessions may stabilise the ‘‘psychedelic afterglow’’ and thereby prolong therapeutic gains. The authors acknowledge key limitations. No placebo or non‑ketamine control arm was included in this trial, so effects attributable to ketamine per se cannot be disentangled from those of psychotherapy or nonspecific factors in this dataset; however, they cite a prior study in which high‑dose ketamine outperformed an active placebo. Randomisation occurred after the initial KPT session and six early relapses prior to allocation could influence comparability; the authors note that including those six with the single‑session cohort would lower the single‑session abstinence rate further. Another limitation is that psychometric measures used in the study did not detect differences between groups, suggesting that the mechanism by which multiple sessions improve abstinence may involve shifts in attitudes or life‑meaning (the afterglow) that were not captured by the instruments employed. In terms of clinical implications, the investigators suggest that multiple KPT sessions merit further study as a promising approach for heroin dependence, and they note that the multiple‑session abstinence rate compares favourably with published outcomes for oral naltrexone in similar contexts. They recommend future research to include control conditions and measures better able to quantify the putative afterglow or changes in life‑view, and they emphasise ongoing attention to safety monitoring given the acute cardiovascular effects observed during sessions.