Extracellular flux analysis and proteomic profiling indicate ibogaine promotes synaptic plasticity and neural repair by a metabolic preconditioning mechanism
Madison J Oulton, Gracious D. S. Kasheke, Kelly A. Meaney, Robyn A. Arseneault, Abhi Pushparaj, Jonathan Dickinson, Christopher S. Hughes, George S. Robertson
bioRxiv (Cold Spring Harbor Laboratory) October 2, 2026 preprint DOI: 10.64898/2026.09.29.755437 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Population | Mouse cortical neurons and female mice |
|---|---|
| Intervention | Ibogaine |
| Dose | 3, 10 or 30 μM; 100 mg/kg |
| Duration | 4-hour treatment with assessment 20 hours later; 0.25-72 hours after oral administration |
| Topics | Ibogaine Neuroplasticity |
| Key points | Ibogaine produced rapid, concentration-dependent metabolic suppression followed by a delayed rebound in energy production in mouse cortical neurons, and oral ibogaine in female mice caused transient spinal cord protein changes consistent with metabolic stress that resolved by 72 hours. The authors propose that this metabolic preconditioning may enhance synaptic plasticity and neural repair, possibly through mitoKv1.3 and the sigma-2 receptor. |
Abstract
We have examined how ibogaine may enhance synaptic plasticity and neural repair. Extracellular efflux analysis showed that ibogaine (3, 10 or 30 μM) produced a rapid (<5 minutes) and concentration-dependent suppression of mitochondrial function and glycolysis in mouse cortical neurons. Cell-based imaging demonstrated this metabolic inhibition was preceded by an elevation of the mitochondrial membrane potential and followed by increased mitochondrial reactive oxygen species levels. Like ibogaine, which blocks potassium channels, mitochondrial Kv1.3 channel (mitoKv1.3) inhibitors produce concordant changes over a similar timeframe. Following treatment with ibogaine (3, 10 or 30 μM) for 4 hours, a marked concentration-dependent rebound of energy production occurred 20 hours later suggestive of metabolic preconditioning. Indeed, proteomic profiling showed that oral ibogaine (100 mg/kg) administration to female mice produced changes in spinal cord protein abundance indicative of increasing metabolic stress from 0.25-24 hours that resolved by 72 hours. This was accompanied by activation, inhibition and reactivation of synaptic plasticity and neural repair signaling pathways at 0.25, 4-24 and 72 hours, respectively. Hence, by inducing transient metabolic stress, ibogaine may re-open a neurodevelopmental window characterized by enhanced synaptic plasticity and neural repair. Ibogaine binds with high affinity to the sigma-2 receptor. Like mitoKv1-3 inhibitors and sigma-2 receptor ligands, ibogaine transiently elevated AMP-activated protein kinase (0.25 hours) and temporally suppressed mechanistic target of rapamycin and lipid synthesis pathways (0.25-24 hours) implicated in enhanced synaptic plasticity and neural repair. These findings suggest ibogaine rewires and repairs neural circuits by a metabolic preconditioning mechanism, perhaps involving mitoKv1.3 and the sigma-2 receptor.