Non-randomized rapamycin augmentation of chronic self-administered ketamine provides subjective improvement in diverse phenotypes

Background: Multiple preclinical and clinical reports suggest that rapamycin augmentation may increase the safety and efficacy of ketamine treatment. Population variability in patient biochemical gain-of-function and phenotypic admixtures, however, has slowed initial investigations into patient selection and dose finding.

Methods: A single-center, retrospective chart review identified 101 patients with ketamine use longer than 2 months. Correlational relationships between demographics, biometrics, ketamine use, concurrent medication use, and serum and tissue biomarkers were obtained in an attempt to characterize this group, given that likely severe selection bias limits generalizability. Rapamycin augmentation was attempted in 38 of these patients. Response was defined by patient preference for continuation and asymptotic dosing.

Results: Ketamine dosing (mean 4.4 ± 3.9 mg/kg/day) ranged widely from 0.4 to 20.7 mg/kg/day. Chronic ketamine use correlated with concurrent opioid use and was possibly associated with various tissue indices of mitochondrial activity. Among 38 patients who attempted rapamycin augmentation, 22 reported phenotypic benefit. Average dose was 1.5 ± 0.95 mg. Phenotypic response was highly variable, with improvement in cognition, fatigue, mood, pain, and dysautonomia. Rapamycin response correlated with weight and absence of antipsychotic use.

Conclusion: Rapamycin and ketamine in combination provide subjective benefit in a select, narrow population. The generalizability of these findings cannot be estimated easily. Subsequent randomized trials may consider using modal dosing as an exploratory endpoint and/or biomarkers, which may have greater utility than phenotypic checklists. These biomarkers could reflect ketamine’s action on complex 1 activity in presynaptic glutamatergic terminals and/or joint effects with rapamycin on homeostatic microglia.