Dichloroacetate (DCA)
A small molecule that inhibits pyruvate dehydrogenase kinase (PDK), reactivating pyruvate dehydrogenase and forcing glucose oxidation over glycolysis and fatty-acid oxidation. Studied for congenital lactic acidosis, pulmonary hypertension and cancer metabolism, but limited by dose-related reversible peripheral neuropathy.
01 Overview
Dichloroacetate inhibits pyruvate dehydrogenase kinase, which normally suppresses the pyruvate dehydrogenase complex. By disinhibiting PDH, DCA drives pyruvate into the mitochondria for oxidation, lowering lactate and shifting cells from glycolysis toward complete glucose oxidation. This makes it a genuine metabolic modulator with an anti-ischaemic and lactate-lowering profile.
It has been used in congenital lactic acidosis and studied in pulmonary arterial hypertension and as an experimental anticancer agent (reversing the Warburg effect). Clinical enthusiasm, including unregulated self-medication in cancer patients, has been tempered by dose-limiting reversible peripheral neuropathy. It remains investigational.
02 Mechanism
Inhibits pyruvate dehydrogenase kinase (PDK), activating the pyruvate dehydrogenase complex to promote oxidation of pyruvate, lowering lactate and shifting metabolism toward glucose oxidation.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Investigational | 12.5–25 mg/kg/day | Oral | Body-weight-based trial dosing, often ~12.5 mg/kg twice daily; investigational only. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Lactate reductionReliably lowers blood lactate in congenital and acquired lactic acidosis. | significant | Clinical | |
| Metabolic shift to glucose oxidationReverses the Warburg-type glycolytic phenotype in preclinical tumour and pulmonary-hypertension models. | Preclinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Sedation and confusionCNS depression reported at higher doses. | Mild | Uncommon | Clinical | |
| Reversible peripheral neuropathySensorimotor neuropathy is the principal dose-limiting toxicity. | Moderate | Dose-limiting | Clinical |