Pyridoxine/pyridoxal-5'-phosphate repletion to improve outcomes of alcohol withdrawal syndrome and promote long-term abstinence: a hypothesis.

INTRODUCTION: Deficiency of pyridoxal-5'-phosphate, the clinically measured and active form of pyridoxine (vitamin B6), is prevalent among those with alcohol use disorder. However, unlike thiamine, pyridoxal-5'-phosphate is not routinely repleted. Evidence is presented that its repletion would improve outcomes of alcohol withdrawal syndrome and promote long-term abstinence.

PYRIDOXAL-5′-PHOSPHATE DEFICIENCY CAN CAUSE A CLINICALLY CONSEQUENTIAL GLUTAMATERGIC/GABAERGIC SIGNALING IMBALANCE: Excessive excitatory glutamatergic signaling and inadequate inhibitory GABAergic signaling are central to the pathophysiology of alcohol withdrawal syndrome. Pyridoxal-5'-phosphate is an essential cofactor for the rate-limiting enzyme in the conversion of glutamate to GABA, glutamic acid decarboxylase. Therefore, pyridoxal-5'-phosphate deficiency would be expected to exacerbate the signaling imbalance that underlies alcohol withdrawal syndrome, worsening symptoms and treatment response. This is supported by the finding that pyridoxal-5'-phosphate deficiency-whether in animal models or other clinical conditions, including nutritional pyridoxine insufficiency, isoniazid toxicity, and certain inborn errors of metabolism-can create a glutamatergic/GABAergic imbalance severe enough to cause anticonvulsant-refractory status epilepticus.

MECHANISMS OF PYRIDOXAL-5′-PHOSPHATE DEFICIENCY IN ALCOHOL USE DISORDER: Pyridoxal-5'-phosphate deficiency in alcohol use disorder occurs in part because alcohol is oxidized by alcohol dehydrogenase to acetaldehyde, which displaces pyridoxal-5'-phosphate from binding proteins, exposing it to hydrolysis by phosphatases. Hepatic disease promotes deficiency through increased phosphatase activity. Other mechanisms, including poor nutritional intake, likely contribute.

PYRIDOXAL-5′-PHOSPHATE DEFICIENCY MAY SURREPTITIOUSLY PRECIPITATE OR EXACERBATE CLINICAL MANIFESTATIONS OF ALCOHOL WITHDRAWAL: In a small study of individuals with alcohol use disorder, pyridoxine deficiency was more prevalent in those who had an alcohol withdrawal seizure than in those who had not. More notably, among patients treated for alcohol withdrawal with the phenothiazine promazine-an obsolete treatment now known to lower the seizure threshold in alcohol withdrawal-supplementation with pyridoxine 120 mg/day resulted in fewer seizures than pyridoxine 20 mg/day (P = 0.02). These findings are consistent with animal models in which pyridoxal-5'-phosphate deficiency lowers the seizure threshold. In another study, of patients who suffered alcohol withdrawal seizures, those who progressed to delirium tremens had lower pyridoxal-5'-phosphate concentrations than those who did not (P = 0.011). Finally, anxiety and confusion are manifestations of both alcohol withdrawal and pyridoxal-5'-phosphate deficiency, presumably in part due to the signaling imbalance common to both. Therefore, these symptoms may be compounded when alcohol withdrawal is superimposed on pyridoxal-5'-phosphate deficiency.

TREATMENT OF PYRIDOXAL-5′-PHOSPHATE DEFICIENCY IN ALCOHOL WITHDRAWAL SYNDROME: The established effectiveness and safety of intravenous pyridoxine in treating seizures and other symptoms resulting from pyridoxal-5'-phosphate deficiency caused by nutritional pyridoxine insufficiency, isoniazid toxicity, and inborn errors of metabolism provide proof of concept that pyridoxine supplementation may safely reduce the severity of alcohol withdrawal syndrome and enhance the response to treatment of those who are deficient. Indeed, seizures resulting from these other causes of pyridoxal-5'-phosphate deficiency remain refractory to benzodiazepines and phenobarbital until administration of pyridoxine, suggesting that some patients with treatment-refractory alcohol withdrawal syndrome would become treatment-responsive after pyridoxine treatment.

PYRIDOXAL-5′-PHOSPHATE DEFICIENCY MAY INCREASE ALCOHOL CRAVING: In addition to causing a glutamate/GABA imbalance, pyridoxal-5'-phosphate deficiency may decrease CNS serotonin through inhibition of aromatic L-amino acid decarboxylase. Both effects can cause anxiety, stress sensitivity, and dysphoria, contributing to craving. Repletion may attenuate these symptoms and, thereby, reduce craving.

DISCUSSION: Pyridoxal-5'-phosphate deficiency produces an excitatory/inhibitory imbalance by impairing the conversion of glutamate to GABA-an imbalance that in other clinical contexts can manifest as anticonvulsant-refractory seizures. It is therefore unlikely that pyridoxal-5'-phosphate deficiency always remains clinically silent during alcohol withdrawal. Moreover, during non-withdrawal abstinence, pyridoxal-5'-phosphate deficiency may cause a glutamate/GABA imbalance and low serotonin, possibly triggering anxiety, stress sensitivity, and dysphoria, thereby increasing craving.

CONCLUSION: Pyridoxal-5'-phosphate repletion in alcohol use disorder warrants investigation.