Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up

Krupitsky and colleagues situate their study within a body of work suggesting that drug-assisted, or psychedelic, psychotherapy can enhance conventional psychotherapy and may have particular utility in addiction treatment. Earlier clinical reports from the 1960s and 1970s, more recent studies of ketamine in alcoholism, and anecdotal evidence for ibogaine indicate possible anti-craving and transformative effects, but methodological heterogeneity, legal constraints and concerns about toxicity for some compounds have limited replication. The authors note specific practical reasons for studying ketamine in Russia: a recent heroin epidemic linked to HIV, and the legal prohibition of opioid agonist maintenance therapies such as methadone and buprenorphine, leaving few treatment options beyond naltrexone and psychosocial approaches. This paper reports a double-blind, randomised clinical trial comparing ketamine psychotherapy (KPT) using a psychedelic, high dose (2.0 mg/kg intramuscular) with an active, sub-psychedelic low dose (0.20 mg/kg intramuscular) in 70 detoxified intravenous heroin addicts. The investigators aimed to test whether a full psychedelic ketamine experience combined with existentially oriented psychotherapy produced greater abstinence, larger reductions in craving, and more pronounced psychological and nonverbal emotional changes than the same psychotherapy paired with a low, active-placebo ketamine dose, with follow-up extending to 24 months.

The study used a double-blind, randomised design with 70 detoxified heroin-dependent inpatients recruited from the Leningrad Regional Centre of Addictions. After detoxification and informed consent, subjects were randomly assigned to a high dose group (35 subjects, 2.0 mg/kg im ketamine) or a low dose group (35 subjects, 0.20 mg/kg im ketamine). Both psychotherapist and subject were blind to dose, and an independent blinded clinical evaluator performed psychological and clinical assessments. The low dose was intended as an active placebo: pharmacologically active but not producing a full psychedelic experience. Eligibility required current heroin dependence for at least one year (ICD-10/DSM-IV), age 18–30, at least high school education, at least two weeks abstinence prior to treatment, absence of psychotropic medication, and availability of a relative for follow-up. Exclusion criteria included major psychotic or affective disorders, seizure disorder, significant medical comorbidity, pregnancy, alcoholism or polydrug dependence, and other factors that could confound outcomes or increase risk. All subjects underwent formal psychiatric and medical evaluation including blood chemistry, HIV test, EKG and urine analysis. The psychotherapeutic intervention comprised three stages: about 10 hours of preparatory psychotherapy, a single ketamine-assisted session lasting roughly 1.5–2 hours with eyeshades, preselected music and active psychotherapeutic support, and about 5 hours of integration psychotherapy in the days after the session. Sessions were conducted by a psychiatrist trained in KPT together with an anaesthesiologist present for safety. Subjects were discharged within 3–5 days after KPT. A broad battery of Russian-adapted instruments was used to assess acute drug effects, psychiatric symptoms and psychological change. Key measures included the Hallucinogen Rating Scale (HRS) for acute subjective drug effects; Zung Depression Scale (ZDS); Spielberger State-Trait Anxiety Scale (SAS); Visual Analog Scale of Craving (VASC); Scale of Anhedonia (SA); MMPI; Locus of Control Scale (LCS); Color Test of Attitudes (CTA) for nonverbal emotional attitudes; Purpose-in-Life Test (PLT); and the Spirituality Changes Scale (SCS). ZDS, SAS, VASC, SA, MMPI, LCS, CTA and PLT were administered at baseline and during the week after the ketamine session. HRS and SCS were administered post-therapy only. ZDS, SAS and VASC were reassessed at 1, 3, 6, 12, 18 and 24 months in subjects who remained abstinent; subjects who relapsed were generally unavailable for later psychometric assessments. Follow-up information was collected monthly up to 24 months by psychiatrists blind to dose and included patient self-report, reports from relatives or colleagues, inspection for injection marks, and urine drug testing at prespecified intervals. The primary outcome was rate of abstinence versus relapse over 24 months. Statistical analyses used repeated-measures ANOVA for within-subject comparisons (with LSD post-hoc tests) and Student's t-test for between-group comparisons, implemented in STATISTICA software. Psychometric measures were treated as secondary outcomes.

Acute experience: The Hallucinogen Rating Scale indicated that the high dose (2.0 mg/kg) produced a full psychedelic experience in heroin-dependent patients, with HRS scores comparable to those reported for classic psychedelics in prior research. HRS scores in the low dose group showed pharmacological effects but fell short of a full psychedelic profile. All HRS subscales differed significantly between groups except the Volition subscale, which the authors note has known sensitivity issues. Primary outcome — abstinence and relapse: The high dose group achieved a significantly higher rate of abstinence and a lower rate of relapse than the low dose group across most time points during the 24-month follow-up. Group differences were statistically significant starting at month 1 and persisted for almost the entire 24-month period. The authors report that almost 50% of patients in the high dose group and about 60% of patients in the low dose group relapsed within the first 3 months after KPT. Craving and anhedonia: Both groups showed significant reductions in heroin craving as measured by the Visual Analog Scale of Craving immediately after KPT. The high dose group experienced significantly larger reductions in craving than the low dose group immediately after treatment and at 1 and 3 months; the high dose group also showed a significant reduction in craving at the two-year follow-up, whereas the low dose group's reduction persisted only to the first month. Scores on the Scale of Anhedonia decreased significantly in both groups across affective, cognitive and behavioural subscales, but between-group differences on anhedonia subscales were not statistically significant. Anxiety, depression and personality measures: State and trait anxiety (Spielberger SAS) were significantly reduced from baseline in both groups and were within normal limits by 3–24 months among those abstaining; no significant between-group differences were observed. Depressive symptoms (Zung) also decreased significantly in both groups without group differences. MMPI profiles improved after treatment in both groups: high dose subjects showed decreases on scales including depression, hysteria, paranoia and schizophrenia-related scales and an increase in self-sufficiency; low dose subjects showed decreases across several scales as well. There were no significant between-group differences on MMPI scores, although the low dose group showed increases on the Lie scale and decreases on a Validity scale, which the authors suggest may reflect greater social desirability responding rather than deeper personality change. Locus of control, purpose and spirituality: Both groups shifted toward a more internal locus of control after KPT; the high dose group showed a statistically significant increase in internality in the domain of failures. Measures of life meaning, life purpose and self-actualisation (PLT) increased significantly in both groups, with no significant differences between doses. Spirituality (SCS) scores rose in both groups to an extent comparable with changes previously observed after KPT in alcoholics. Non-verbal emotional attitudes (CTA): The Color Test of Attitudes showed greater positive changes in nonverbal/unconscious emotional attitudes in the high dose group: seven of nine images showed significant positive change versus four of nine in the low dose group. The authors interpret this as stronger incorporation of attitudes related to abstinence after high dose KPT. Safety: No serious adverse events such as protracted psychosis or flashbacks occurred, and none of the participants developed ketamine dependence. The only noted physiological side effect was an acute increase in systolic and particularly diastolic blood pressure of approximately 20–30% during the session. The study team reports no complications requiring intervention.

Krupitsky and colleagues interpret their findings as evidence that ketamine-assisted psychotherapy using a high, psychedelic dose produces superior long-term abstinence and longer-lasting reductions in craving compared with the same psychotherapy combined with a low, sub-psychedelic ketamine dose. They emphasise that many psychometric changes occurred in both groups, indicating that the psychotherapy common to both conditions contributed importantly to clinical improvement. The authors highlight that the high dose produced acute subjective effects on the Hallucinogen Rating Scale similar to those induced by classic psychedelics, whereas the low dose functioned more as ketamine-facilitated guided imagery. They discuss the role of set and setting, noting that even low doses in a supportive therapeutic context can yield meaningful experiences. The paper links possible anti-craving effects to ketamine's action at the NMDA receptor, drawing parallels with other NMDA ligands such as ibogaine and acamprosate. Safety and tolerability are discussed favourably: no prolonged psychosis or ketamine addiction occurred, and adverse events were limited to transient blood pressure increases. The authors suggest that excluding patients with comorbid psychiatric disorders may have reduced risk and that ketamine's pharmacology may differ from serotonergic psychedelics in ways that influence safety. Limitations and implications for future research are acknowledged. The investigators note that many secondary measures did not differ between groups, the inability to assess psychometrics in participants after relapse limited longitudinal measurement, and that a single ketamine session may be insufficient since substantial relapse occurred within the first months. They propose testing repeated KPT sessions and further work to determine how best to harness the psychedelic experience to promote sustained abstinence. The authors also suggest that ketamine-elicited spiritual or transformative experiences may contribute to recovery in a manner analogous to near-death experiences or spiritual conversions reported in other contexts.