Functional Assessment and Treatment of Alcohol Use Disorders

Introduction

Alcohol use disorders (AUD) are a major preventable cause of morbidity and mortality. Effective interventions exist ; however, there are many barriers to optimal outcomes. Well-established psychosocial and pharmacological interventions for AUD can be limited by disengagement, tolerability, nonadherence, and high relapse rates. There is a need for additional interventions that are safe, well tolerated, acceptable to patients, and effective. Natural molecular treatments—or functional treatments, such as high-dose vitamins, minerals, amino acids and other metabolites—are supported by several lines of evidence and may engage patients who are reluctant to accept pharmaceutical medications. Such interventions are not a replacement for effective pharmacotherapy or psychosocial interventions, but they may have salutary benefits, support recovery, and engage patients in fostering nutritional health. This chapter explores the rationale supporting functional treatments in AUD and clinical considerations in assessment and treatment. After describing functional medicine in general, we characterize four natural interventions for which there is evidence of efficacy, followed by a series of less well-established interventions that warrant consideration.

Functional Treatment Defined

Functional Medicine (FM) is not a separate branch of medicine, such as Ayurveda, acupuncture, or energy healing, disciplines that are sometimes referred to as complimentary, holistic, or alternative medicine. FM approaches disease in a manner consistent with Western medical paradigms, addressing pathophysiologic mechanisms in disease to reduce pathology and support restoration of health. However, FM prioritizes use of commonly available nutritional entities to address imbalances with perceived incremental negative effect over time. Typical interventions include vitamins, minerals, and nutrients.

Why Are Functional Treatments Important in AUD

Alcohol is one of the oldest known intoxicating substances used by humans. Excessive alcohol use can have both acute and chronic toxic effects. Gastrointestinal enterocytes may become degraded, impairing barrier function and leading to absorption of inflammatory bacterial cell-wall components (e.g., lipopolysaccharide). Hepatic toxicity, as well as innate immune system hyperstimulation, may contribute to the development of cirrhosis. Gut-related toxicity inhibits absorption of numerous vitamins, minerals and nutrients, leading to deficiencies not easily corrected through low-dose oral repletion strategies. Renal toxicity may decrease reabsorption or increase excretion of necessary nutrients, compounding the effect of impaired intestinal absorption. Thus, alcohol may both cause and magnify nutritional deficiencies in drinkers. Excessive alcohol use can deplete vitamin and mineral cofactors, leading to deficiencies and degradation of antioxidant systems, leaving tissues vulnerable to free-radical and inflammatory assault. Recognizing patterns of AUD toxicity and understanding the role of nutritional depletion sets the stage for functional treatment.

Thiamine

Thiamine, also known as Vitamin B1, is a coenzyme required by several enzymes critical to energy metabolism. Thiamine is found in whole grains, yeast, and legumes and is absorbed in the small intestine via active transport and passive diffusion. Thiamine has a half-life of 10–20 days, and its metabolites are excreted via urine and bile. Thiamine storage is limited, necessitating continuous dietary consumption to maintain adequate levels. Deficiency may result from inborn errors of metabolism, poor absorption, or inadequate nutrition.

The best-known complication of severe thiamine deficiency in persons with AUD is Wernicke’s encephalopathy, an acute neurological syndrome characterized by progressive encephalopathy, oculomotor dysfunction, and gait ataxia; unaddressed, this can lead to long-term complications such as Korsakoff's dementia. However, subclinical thiamine deficiency is much more common in AUD and may still have significant neurological consequences.

Thiamine is poorly phosphorylated to its active diphosphate form in the context of inadequate nutrition and hepatic insufficiency, reducing its activity as an essential cofactor for a number of enzymes in the tricarboxylic acid cycle. Deficiency reduces dependent enzymatic activity, but it also reduces overall concentrations of both thiamine-dependent and thiamine-independent enzymes in the murine tricarboxylic acid cycle. Thiamine deficiency degrades ATP productive capacity, which contributes to neuronal injury, particularly in the mammillary bodies, impairs cardiac function, and compromises other vulnerable tissues and organ systems. Direct toxic effects of thiamine deficiency are further compounded by indirect effects that increase oxidative stress.

Most commercial laboratories offer serum thiamine testing, with a normal range of 70–180 nmol/L (3.0–7.7 μg/dL). Thiamine deficiency can be detected through an inadequate erythrocyte thiamine transketolase response to a thiamine pyrophosphate challenge test. However, the sensitivity and specificity of this test is not well characterized, nor is it readily available at point of care. Cerebral spinal fluid thiamine monophosphate levels are potentially more sensitive and specific for thiamine deficiency ; however, these too are impractical in general practice when a clinical determination is sufficient to justify supplementation.

Thiamine is readily available over the counter for oral intake and by prescription for parenteral administration. It is low cost, well tolerated, and indicated in the treatment of acute alcohol detoxification. Normal dietary requirements are 1–2 mg daily; however, in the setting of insufficiency, significantly higher levels of repletion are required. A recent systematic review concluded there is insufficient evidence to dictate specific recommendations for dose, frequency, or route of thiamine administration. However, the Royal College of Physicians published a rigorous guideline for treatment and prevention of Wernicke's encephalopathy, recommending parenteral thiamine dosing of 500–750 mg three times per day for a minimum of 5 days, and to continue for as long as improvement occurs. They also recommend parenteral administration of riboflavin, pyridoxine, nicotinamide, vitamin C, and magnesium. Other recommendations suggest 500 mg thiamine parenterally three times per day for 2 days, followed by 250 mg parenterally for 5 days. Supplementation of thiamine should precede glucose administration, as glucose metabolism depletes thiamine and can exacerbate deficiency.

Oral thiamine is poorly absorbed, such that treatment of AUD in outpatient settings should include high-dose oral thiamine supplementation or use of highly absorbed thiamin congeners, such as benfotiamine. Benfotiamine (S-benzoylthiamine-O-monophosphate) is a high-potency thiamine analog found within the allium family (e.g., garlic, onions, leeks). It is the most studied and most potent of the allithiamines, a class of natural thiamine congeners with enhanced absorption and blood–brain barrier penetration (e.g., benfotiamine, sulbutiamine, fursultiamin). These thiamine analogs are of particular interest in AUD because they offer increased absorption in compromised individuals. A study of 120 nontreatment seeking, actively drinking, alcohol-dependent adults found that 600 mg daily oral benfotiamine was well tolerated and was associated with a significant reduction in total mean alcohol intake over 6 months (−611 drinks vs. −159 drinks) in women, but not in men. A study at a teaching hospital found that inadequate thiamine repletion was documented in 97.6% of high-risk inpatients, resulting from inappropriate dosing, frequency and route of delivery. Given the favorable risk-benefit profile of thiamine, supplementation should be considered for all patients with moderate to severe alcohol use disorder.

N-acetylcysteine

N-acetylcysteine (NAC) is a low-cost, well-tolerated dietary supplement, available both over-the-counter and by prescription. NAC is a prodrug to l -cysteine, the limiting amino acid precursor to the endogenous antioxidant glutathione. NAC is FDA approved to prevent hepatic injury after acetaminophen overdose and is believed to exert its protective effects through restoration of glutathione levels depleted by the toxic acetaminophen metabolite N-acetyl-p-benzoquinoneimine. NAC has shown promise in several psychiatric conditions and substance use disorders.

Both cysteine and glutathione can become depleted in AUD. Low consumption of protein or poor digestive function can limit absorption. In addition, hepatic insufficiency can impair transsulfuration, which is required to recover cysteine from homocysteine. One marker of depletion is gamma-glutamyl transferase (GGT), which is used as a marker of excessive drinking because GGT increases as the body attempts to restore alcohol-related depletion of cysteine and glutathione. Glutathione also plays a direct and essential role in NMDA receptor activity through regulation of many redox sensitive processes, such as receptor activation and signal transduction. NMDA receptor hyperactivity may mediate acute and postacute alcohol withdrawal symptoms and influence long-term mood regulation and risk of relapse.

To date, most research on NAC in AUD has focused on alcoholic hepatitis. One study evaluated 5 days of IV NAC versus placebo given with prednisolone in 174 human subjects with severe alcoholic hepatitis, reporting a notable decrease in 1-month all-cause mortality (hazard ratio, 0.58; 95% CI, 0.14 to 0.76; P = .006) though their primary outcome measurement at 6 months fell short of significance (hazard ratio, 0.62; 95% CI, 0.37 to 1.06; P = .07). However, given that functional interventions are unlikely to continue working for 6 months after only 5 days of treatment, the duration of administration may not have been adequate. In future research, transition to oral NAC dosing might be considered.

Typical dosing for NAC is 1200 mg orally twice daily; however, doses as high as 8000 mg/day have been administered safely and without adverse effects. A double-blinded randomized controlled study of NAC at 2400 mg/day in veterans with post-traumatic stress disorder and SUD (over 80% had AUD) demonstrated improvements in clinical scores for depression, PTSD and drug craving (alcohol, cocaine and opiate; P < .05), though craving was a secondary outcome.

At this point in time, there is not much direct evidence to support the use of NAC for AUD. However, as the preceding discussion indicates, there are several reasons why NAC may be therapeutic, and additional studies are warranted to examine its efficacy. Clinicians may consider using NAC on a case by case basis, weighing the positive safety profile against the potential, but as of yet unproven, benefits.