A Comprehensive Monograph on Metadoxine (DB16554)

1.0 Executive Summary

Metadoxine is a small molecule drug with a unique chemical identity as an ion-pair salt of pyridoxine (vitamin B6) and L-2-pyrrolidone-5-carboxylate (pyroglutamic acid). This composition underpins a multifaceted mechanism of action that confers both hepatoprotective and neuromodulatory effects. The drug's primary therapeutic application, established over decades of use in several European and other nations, is in the management of acute and chronic alcohol-related disorders. Clinical evidence supports its efficacy in accelerating the clearance of ethanol and its toxic metabolite, acetaldehyde, thereby shortening recovery time from acute intoxication. Furthermore, it has demonstrated significant utility in treating alcoholic liver disease, including alcoholic fatty liver and severe alcoholic hepatitis, where it improves liver function, reduces steatosis, and has been shown to improve short-term survival when used as an adjunct to standard therapy. A notable feature is its apparent efficacy even in patients who have not achieved complete abstinence from alcohol.

The pharmacological profile of Metadoxine is complex. Its hepatoprotective actions are attributed to the restoration of hepatic glutathione and adenosine triphosphate (ATP) levels, antioxidant effects that mitigate oxidative stress, and anti-inflammatory properties such as the attenuation of TNF-α secretion. Concurrently, its neuromodulatory effects are linked to its activity as a modulator of the GABAergic system—by inhibiting GABA transaminase and enhancing GABAergic transmission—and as a selective antagonist of the 5-HT2B serotonin receptor.

Despite its established role in alcohol-related conditions, Metadoxine's development history is marked by a significant and ultimately unsuccessful attempt to reposition the drug for the treatment of neurodevelopmental disorders. An extended-release formulation (MDX) was developed to overcome the molecule's inherently short pharmacokinetic half-life (approximately 1 hour) and was advanced into late-stage clinical trials for Attention-Deficit/Hyperactivity Disorder (ADHD) and Fragile X Syndrome (FXS). Despite promising Phase II data, the pivotal Phase III trial for ADHD failed to meet its primary efficacy endpoints. This failure, compounded by the imposition of a clinical hold by the U.S. Food and Drug Administration (FDA) due to neurotoxicity findings in long-term animal studies, led to the cessation of its development for these indications. Similarly, trials in non-alcoholic steatohepatitis (NASH) failed to demonstrate significant benefits on liver histology.

Consequently, Metadoxine occupies a dichotomous position in the global pharmaceutical landscape. It is not approved by the FDA in the United States or the Therapeutic Goods Administration (TGA) in Australia for any indication. However, it holds national marketing authorizations in several European countries, such as Italy, Hungary, and Portugal, for the treatment of alcohol intoxication and alcoholic liver disease. Its safety profile in humans for short-term use is generally favorable, characterized primarily by mild gastrointestinal side effects. However, significant gaps remain in the understanding of its oral pharmacokinetics, and the unresolved preclinical safety concerns cast a shadow over its potential for long-term use. This report provides a comprehensive analysis of the chemistry, pharmacology, clinical evidence, and regulatory history of Metadoxine, concluding that its therapeutic value is firmly established within the niche of alcohol-related disorders, while its potential for broader applications remains unproven.

2.0 Introduction and Chemical Identity

2.1 Overview and Development History

Metadoxine, known chemically as pyridoxine-pyrrolidone carboxylate, is a therapeutic agent principally utilized in the management of conditions arising from excessive alcohol consumption, including both acute alcohol intoxication and chronic alcoholic liver disease.[1] Its history spans more than three decades, during which it has been predominantly used in specific European countries and other developing nations for these indications.[4] The drug's established role is based on its ability to accelerate the clearance of alcohol from the bloodstream and mitigate its toxic effects on the liver and central nervous system.[2]

In recent years, Metadoxine became the subject of a significant drug repositioning effort, wherein its neuromodulatory properties were explored for the treatment of neurodevelopmental disorders. This led to the development of a novel extended-release formulation and a series of clinical trials investigating its efficacy in Attention-Deficit/Hyperactivity Disorder (ADHD) and Fragile X Syndrome (FXS).[2] This development path created a dichotomy in the drug's identity: a long-established therapy for alcohol-related pathologies in some parts of the world, and a modern investigational drug for psychiatric conditions in others. As this report will detail, this latter effort ultimately proved unsuccessful, framing the narrative of Metadoxine as a compound with a well-defined niche utility that failed to translate to broader, more complex therapeutic areas.

2.2 Chemical Structure and Composition

Metadoxine possesses a unique chemical structure as an ion-pair salt, formed through the in vitro process of salification between two distinct, naturally occurring molecules: L-2-pyrrolidone-5-carboxylate (commonly known as pyroglutamic acid, or PCA) and pyridoxine (a vitamer of vitamin B6).[2] These two components are present in a 1:1 equimolar ratio and are linked by an electrostatic interaction rather than a covalent bond, with the acidic PCA acting as the anion and the basic pyridoxine acting as the cation.[7] This structure is fundamental to understanding the drug's broad pharmacological profile, as the biological activities of its constituent parts are believed to contribute synergistically to its overall therapeutic effect.[7]

The individual components are biologically significant:

• Pyridoxine (Vitamin B6): This is a water-soluble vitamin that serves as a precursor to pyridoxal 5'-phosphate (PLP), an essential coenzyme in a vast array of metabolic processes. PLP is critically involved in the metabolism of amino acids, carbohydrates, and lipids. In the context of Metadoxine's indications, it plays a role in the metabolic degradation of ethanol and is a required cofactor for the synthesis of several key neurotransmitters, including dopamine, serotonin (5-HT), norepinephrine, epinephrine, and gamma-aminobutyric acid (GABA).[2]
• L-Pyroglutamic Acid (PCA): This is a derivative of the amino acid glutamic acid. It is an important intermediate in the gamma-glutamyl cycle, a pathway responsible for the synthesis and degradation of the master antioxidant glutathione (GSH).[7] Its presence in the Metadoxine salt provides a direct link to the drug's ability to modulate cellular redox status and protect against oxidative stress.

The systematic (IUPAC) name for this compound is (2S)-5-oxopyrrolidine-2-carboxylic acid; 4,5-bis(hydroxymethyl)-2-methylpyridin-3-ol.[6] Its structure is represented by the following chemical identifiers:

• Canonical SMILES: CC1=NC=C(C(=C1O)CO)CO.C1CC(=O)N[C@@H]1C(=O)O [10]
• InChIKey: RYKKQQUKJJGFMN-HVDRVSQOSA-N [6]

2.3 Identification and Nomenclature

Metadoxine is cataloged across major chemical and pharmacological databases under several key identifiers that ensure its unambiguous identification for research, clinical, and regulatory purposes.

Primary Identifiers:

• DrugBank Accession Number: DB16554 [6]
• CAS Registry Number: 74536-44-0 [6]
• FDA Unique Ingredient Identifier (UNII): EJQ7M98H5J [6]
• KEGG ID: D08186 [10]
• ATC Code: A05BA09 [14]

Synonyms and Trade Names:

The drug is known by a variety of synonyms and commercial brand names, reflecting its long history and availability in different markets. These include:

• Pyridoxine pyroglutamate [6]
• Metadoxil [2]
• Metasin [12]
• Metadoxin [12]
• Alcoliv [1]
• Reheptin [1]
• Metadoxil 500Mg Tablet [1]
• Toneliv 500Mg Tablet [1]
• Livodox [1]

3.0 Physicochemical and Pharmaceutical Properties

3.1 Key Physicochemical Data

The physicochemical properties of Metadoxine define its behavior in biological systems and are crucial for its formulation into effective dosage forms. It exists as a white to light yellow solid powder.[14] Key properties are summarized in Table 1. Its high water solubility is notable, facilitating its formulation as both an oral solid and an injectable solution.[16] The negative logP value indicates its hydrophilic nature, consistent with its component molecules.[6]

Table 1: Key Identifiers and Physicochemical Properties of Metadoxine

Property	Value	Source(s)
CAS Number	74536-44-0	6
Molecular Formula	$C_{13}H_{18}N_{2}O_{6}$	6
Average Molecular Weight	298.29 g/mol	6
Monoisotopic Mass	298.116486308 Da	6
Physical State	Solid (White to Light Yellow Powder)	14
Melting Point	102-104°C	12
Boiling Point (Predicted)	491.9°C	[18]
Water Solubility	$\geq$ 155 mg/mL	16
logP (Predicted)	-0.95	6
pKa (Strongest Acidic)	9.4	6
pKa (Strongest Basic)	5.58	6
Polar Surface Area	73.58 $Å^{2}$	6
Storage Conditions	Sealed in dry, 2-8°C or <-15°C	[14, 18]

3.2 Formulations and Commercial Preparations

Metadoxine has been developed and marketed in distinct formulations tailored to different therapeutic indications, a strategy that underscores the challenges posed by its pharmacokinetic profile.

• Immediate-Release (IR) Formulations: These are the conventional forms of the drug, available as oral tablets and injectable solutions for intramuscular (IM) or intravenous (IV) administration.[3] The oral tablets typically contain 500 mg of the active ingredient, with a general prescribed dosage of 500-1000 mg per day.[1] The injectable form is used for acute alcohol intoxication, with studies employing doses such as 300 mg IV.[20] These IR formulations are suited for conditions where rapid onset of action is desired.
• Extended-Release (ER) Formulation (MDX): A more recent development was an oral extended-release formulation, referred to as MDX. This formulation was specifically engineered by Alcobra Ltd. to address the drug's very short half-life by combining immediate-release and slow-release components into a single dosage unit.[2] The goal was to prolong the drug's therapeutic window, making it suitable for chronic conditions requiring sustained plasma concentrations, such as ADHD and FXS.[2] Doses used in clinical trials for these indications were significantly higher than those for alcohol-related disorders and were often weight-based, ranging from 700 mg to 1400 mg per day.[5]
• Commercial Brands: In markets where it is approved, such as India, Metadoxine is available under various brand names, including Metadoxil, Alcoliv, Reheptin, and Livodox.[1]

The existence of these two distinct formulation strategies is central to the drug's story. The IR formulation was sufficient for its original purpose in treating acute and chronic alcohol-related issues. However, the attempt to reposition Metadoxine for neurodevelopmental disorders was entirely dependent on the technological ability of the ER formulation to overcome the molecule's inherent pharmacokinetic limitations. The ultimate failure of the MDX clinical program suggests that this formulation strategy, while necessary, was not sufficient to establish efficacy and safety for the new indications.

4.0 Non-Clinical Pharmacology and Mechanism of Action (MoA)

Metadoxine exerts its therapeutic effects through a complex and multi-modal mechanism of action, leveraging the distinct but synergistic properties of its two constituent molecules. Its pharmacological profile can be broadly categorized into hepatoprotective/antioxidant actions, neuromodulatory effects, and direct influence on alcohol metabolism.

4.1 Hepatoprotective and Antioxidant Mechanisms

A core aspect of Metadoxine's pharmacology is its ability to protect the liver from damage induced by toxins, particularly alcohol and its metabolites. This is achieved through several interconnected pathways.

• Redox Homeostasis and Glutathione (GSH) Regulation: Metadoxine acts as an effective antioxidant by preventing the depletion of glutathione, the primary endogenous antioxidant in hepatocytes.[9] Alcohol metabolism consumes GSH, leading to oxidative stress. Metadoxine counters this by restoring GSH levels, a function likely linked to its PCA component, which is an intermediate in the GSH synthesis cycle.[9] This action helps maintain the cellular redox balance and protects against damage from reactive oxygen species.[4]
• Cellular Energy Restoration: Chronic alcohol consumption impairs cellular energy metabolism. Acetaldehyde, a toxic metabolite of ethanol, can inactivate adenosine triphosphate (ATP), the cell's main energy currency. Metadoxine has been shown to prevent this alcohol-induced decrease in ATP concentrations in both the liver and the brain, thereby helping to preserve cellular function and viability.[2]
• Anti-inflammatory and Antifibrotic Activity: Chronic liver injury from alcohol leads to inflammation and the subsequent deposition of collagen, resulting in fibrosis and eventually cirrhosis. Preclinical studies have shown that Metadoxine can interrupt these early pathological events. In cultured hepatic stellate cells (the primary collagen-producing cells in the liver), Metadoxine prevents the acetaldehyde-induced increase in collagen secretion and attenuates the release of the pro-inflammatory cytokine TNF-α.[16] This suggests an ability to modulate the inflammatory and fibrogenic response to alcohol-induced injury.
• Modulation of Lipid Metabolism: Alcoholic liver disease is characterized by the accumulation of fat in the liver (steatosis). Metadoxine has been shown to counteract this process. In animal models, it inhibits the increase of fatty acid esters in the liver of ethanol-treated rats and prevents the formation of fatty liver.[2] This antisteatotic effect contributes to its efficacy in treating alcoholic fatty liver disease.

4.2 Neuromodulatory Effects on GABAergic and Serotonergic Systems

Beyond its effects on the liver, Metadoxine exhibits significant activity within the central nervous system, which provides the rationale for its use in relieving neuropsychological disorders associated with alcohol intoxication and its investigation for ADHD and FXS.

• GABA System Modulation: Metadoxine is described as a monoamine-independent GABA modulator, meaning it influences the GABA system without directly affecting dopamine, norepinephrine, or serotonin levels.[2] Its effects on this primary inhibitory neurotransmitter system are multifaceted:

1. It acts as a modulator of the Sodium- and chloride-dependent GABA transporter 1 (SLC6A1), which is responsible for the reuptake of GABA from the synapse.[6]
2. It reduces the activity of GABA transaminase, the enzyme that degrades GABA, thereby potentially increasing GABA availability in the synapse.[1]
3. Electrophysiological studies have confirmed that it increases inhibitory GABAergic synaptic transmission through a presynaptic mechanism.[2]

• Serotonin System Antagonism: Metadoxine also functions as a selective antagonist of the serotonin receptor subtype 5-HT2B.[1] The 5-HT2B receptor is involved in regulating various physiological functions, and its antagonism may contribute to the drug's overall neuropsychopharmacological profile.
• Cognitive Enhancement: In preclinical studies, Metadoxine demonstrated a cognition-enhancing effect in the rat social recognition model, providing further support for its potential utility in cognitive disorders.[2]

4.3 Influence on Ethanol and Acetaldehyde Metabolism

The most immediate and well-documented effect of Metadoxine is its ability to accelerate the clearance of ethanol and its highly toxic primary metabolite, acetaldehyde, from the blood and tissues.[1] This detoxification action is central to its efficacy in treating acute alcohol intoxication.

• Enzymatic Modulation: The precise mechanism by which it enhances alcohol metabolism is subject to some conflicting reports, suggesting a complex, context-dependent action.
• Animal studies indicate that Metadoxine increases the activity of acetaldehyde dehydrogenase, the enzyme responsible for converting toxic acetaldehyde into less harmful acetate.[2]
• It has also been shown to prevent the decrease in alcohol dehydrogenase (ADH) activity that occurs with chronic ethanol feeding in rats.[2] This suggests a restorative or protective effect on the primary ethanol-metabolizing enzyme.
• However, other sources state that Metadoxine does not directly activate ADH [9], and one in vitro experiment reported that it actually reduced ADH activity.[1] This discrepancy may be due to differences between in vivo and in vitro conditions, dose-dependent effects, or the possibility that its primary metabolic impact is on downstream pathways (e.g., acetaldehyde dehydrogenase) rather than on ADH itself.
• Enhanced Clearance: Regardless of the exact enzymatic mechanism, the net result is an accelerated elimination of ethanol and its metabolites. Metadoxine increases both plasma and urinary clearance of ethanol and promotes the urinary excretion of ketones, which are alternative metabolic byproducts formed during periods of massive alcohol intake.[2]

4.4 Other Pharmacodynamic Effects

• Inhibition of Adipogenesis: Separate from its alcohol-related mechanisms, Metadoxine has been shown to block the differentiation of preadipocytes (fat cell precursors) into mature adipocytes. This effect is mediated by the inhibition of the protein kinase A-cAMP response element binding protein (PKA-CREB) signaling pathway.[2] This mechanism provides a biological rationale for its investigation in metabolic liver diseases not caused by alcohol, such as Metabolic Dysfunction-associated Steatohepatitis (MASH).

The combination of these diverse mechanisms—accelerating toxin clearance, replenishing cellular defenses, reducing inflammation, and modulating neurotransmitter systems—explains Metadoxine's utility in addressing both the acute toxicological and chronic pathophysiological consequences of alcohol abuse.

5.0 Pharmacokinetics and Metabolism (ADME)

5.1 ADME Profile Overview

A comprehensive understanding of the absorption, distribution, metabolism, and excretion (ADME) of Metadoxine is significantly hampered by a lack of publicly available data. Key sections in major drug databases for absorption, metabolism, and route of elimination are explicitly marked as "Not Available," representing a critical knowledge gap for a drug with decades of clinical use.[6] The available information is sparse and derived primarily from studies of intravenous administration, leaving the pharmacokinetics of the more common oral route largely uncharacterized.

• Absorption: There is no specific data provided on the oral bioavailability of Metadoxine or the kinetics of its absorption from the gastrointestinal tract. It is unknown whether the ion pair remains intact during absorption or dissociates into its pyridoxine and PCA components prior to entering systemic circulation.
• Distribution: A pharmacokinetic study in healthy Chinese volunteers following multiple intravenous doses calculated a mean volume of distribution ($V_d$) of 84.4 L.[24] This value, being significantly larger than the volume of blood plasma, indicates that the drug distributes into tissues outside of the vascular compartment.
• Metabolism: The metabolic fate of Metadoxine has not been detailed. The individual components, pyridoxine and PCA, have well-established metabolic pathways, but it is unknown if their metabolism is altered when administered together as an ion-pair salt.[6]
• Excretion: The primary route of elimination for Metadoxine and its potential metabolites is not definitively established.[6] One source suggests it is partially excreted via the kidneys.[25] A study in rats investigated the effect of Metadoxine on the excretion of ethanol and its metabolites in urine and feces, but did not report on the disposition of Metadoxine itself.[8]

5.2 Analysis of Human Pharmacokinetic Studies

The most reliable pharmacokinetic data for Metadoxine in humans comes from two studies involving intravenous administration in healthy volunteers. These studies consistently point to a very rapid elimination profile.

• Study 1 (Lü Yuan et al., 2007): This study examined the pharmacokinetics after repeated IV doses in 10 healthy male subjects. The data fit a standard one-compartment model.[27]
• Half-life ($t_{1/2}$): The elimination half-life was exceptionally short, measured at approximately 0.85 hours after the first dose and 0.77 hours after seven days of dosing.
• Exposure ($AUC_{0-12}$): The area under the concentration-time curve over 12 hours was $25.56 \pm 4.56$ mg·h·L⁻¹ on day 1 and $23.05 \pm 4.74$ mg·h·L⁻¹ on day 7, indicating no significant accumulation.
• Study 2 (Latin American Journal of Pharmacy, 2018): This study evaluated single and multiple IV doses in 12 healthy Chinese volunteers and measured the pyridoxine component of Metadoxine.[24]
• Single-Dose Phase (0.6 g to 1.2 g): The pharmacokinetics were dose-proportional across this range. The maximum plasma concentration ($C_{max}$) increased from a mean of 2.58 µg/mL to 5.44 µg/mL, and the total exposure ($AUC_{0-t}$) increased from 7.54 µg·h/mL to 18.60 µg·h/mL. The terminal half-life was approximately 1.0 hour.
• Multiple-Dose Phase (0.9 g daily for 7 days): The parameters were consistent with the single-dose findings. The mean half-life was 0.82 hours, and the accumulation index was 1.07, confirming minimal drug accumulation with daily dosing.

The extremely short half-life of approximately 0.8 to 1.0 hour is the most defining pharmacokinetic characteristic of Metadoxine. This rapid clearance is well-suited for treating an acute condition like alcohol intoxication, where a fast but transient effect is desired. However, this same property renders the immediate-release formulation therapeutically challenging for chronic conditions like ADHD, which require stable, all-day drug exposure. This fundamental pharmacokinetic limitation was the primary driver for the development of the extended-release (MDX) formulation in the unsuccessful attempt to reposition the drug.

Table 2: Summary of Human Pharmacokinetic Parameters (IV Administration)

Parameter	Value (Mean ± SD)	Study Population	Source(s)
Half-life ($t_{1/2}$)	0.77 ± 0.09 hours	10 healthy males (repeated dose)	27
	0.82 ± 0.13 hours	12 healthy volunteers (repeated dose)	24
	~1.0 hour	12 healthy volunteers (single dose)	24
Max Concentration ($C_{max}$)	3.66 ± 0.74 µg/mL	12 healthy volunteers (0.9g repeated dose)	24
Area Under Curve ($AUC_{0-t}$)	$23.05 \pm 4.74$ mg·h·L⁻¹	10 healthy males (repeated dose)	27
	$12.57 \pm 2.81$ µg·h/mL	12 healthy volunteers (0.9g repeated dose)	24
Clearance (CL)	$72.2 \pm 17.0$ L/h	12 healthy volunteers (repeated dose)	24
Volume of Distribution ($V_d$)	$84.4 \pm 17.1$ L	12 healthy volunteers (repeated dose)	24
Accumulation Index	1.07 ± 0.10	12 healthy volunteers (repeated dose)	24

5.3 Gaps in Current Pharmacokinetic Knowledge

The available data leaves several critical questions unanswered, particularly concerning the oral administration route, which is most common in clinical practice for chronic conditions.

• Oral Bioavailability: The fraction of an oral dose that reaches systemic circulation is unknown. Without this information, it is impossible to accurately relate the oral doses used in clinical trials to systemic exposure and pharmacodynamic effects.
• Food Effect: The influence of food on the rate and extent of Metadoxine absorption has not been studied.
• Metabolic Profile: A detailed characterization of the metabolic pathways of Metadoxine is needed. It is unclear if the ion pair is metabolized intact or if it dissociates, and whether its metabolism differs from that of its individual components administered separately.
• Excretion Mass Balance: A comprehensive mass balance study to identify all routes of excretion (e.g., renal, fecal) and quantify their relative contributions is necessary for a complete ADME profile.

6.0 Clinical Efficacy in Alcohol-Related Disorders

The primary and most well-supported therapeutic role for Metadoxine is in the management of alcohol-related disorders. A body of clinical evidence, including randomized controlled trials, demonstrates its efficacy across a spectrum of conditions from acute intoxication to severe chronic liver disease.

6.1 Acute Alcohol Intoxication

Metadoxine has been shown to be effective in accelerating recovery from acute alcohol intoxication by enhancing the elimination of ethanol and improving associated symptoms.

• A double-blind, randomized, placebo-controlled study by Shpilenya et al. (2002) in 58 patients provides strong evidence for this indication.[28] A single intravenous dose of 900 mg of Metadoxine significantly reduced the half-life of ethanol in the blood compared to placebo (5.41 hours vs. 6.70 hours). This was accompanied by a much faster onset of clinical recovery, with the median time to improvement being 0.95 hours in the Metadoxine group versus 2.34 hours for placebo. Furthermore, patients treated with Metadoxine showed a significantly greater improvement in the clinical symptoms of intoxication at the 2-hour mark.
• An earlier open-label study by Díaz Martínez et al. (2002) evaluated 300 mg of IV Metadoxine as an adjunct to standard therapy.[20] The results showed that a significantly higher percentage of patients receiving Metadoxine improved by at least one clinical category of intoxication compared to those receiving standard treatment alone (76.9% vs. 42.3%). This clinical improvement was correlated with a significantly greater decrease in blood alcohol concentration over the study period.

6.2 Alcoholic Fatty Liver Disease (Steatosis)

Metadoxine has demonstrated efficacy in improving the biochemical and structural markers of alcoholic fatty liver, the earliest stage of alcoholic liver disease.

• A landmark double-blind, placebo-controlled trial conducted by the Spanish Group for the Study of Alcoholic Fatty Liver (Caballería et al., 1998) provides the most robust evidence in this area.[30] In this study, 136 patients with alcoholic fatty liver were treated with 1500 mg/day of Metadoxine or placebo for three months. The Metadoxine group experienced a more rapid and pronounced improvement in liver function tests (bilirubin, aminotransferases, GGT), with significant changes evident after just one month of treatment. Post-treatment ultrasonography revealed that the prevalence of steatosis was significantly lower in the Metadoxine group (28%) compared to the placebo group (70%).
• A critically important finding from this trial was the drug's efficacy in patients who did not fully abstain from alcohol. While the placebo group only showed biochemical improvement in abstinent patients, the Metadoxine group demonstrated similar improvements in both abstinent and non-abstinent patients. This suggests that Metadoxine can act as a harm-reduction agent, mitigating liver damage even in the presence of ongoing, albeit reduced, alcohol consumption. This is a significant clinical differentiator from many other hepatoprotective agents.

6.3 Severe Alcoholic Hepatitis (SAH)

In the most severe form of acute-on-chronic alcoholic liver injury, severe alcoholic hepatitis, Metadoxine has shown a remarkable survival benefit when added to standard-of-care treatments.

• A series of open-label, randomized clinical trials led by Higuera-de la Tijera and colleagues (NCT02161653) evaluated the addition of Metadoxine (500 mg three times daily) to standard therapy with either prednisone or pentoxifylline.[31] In the arm where Metadoxine was added to prednisone, survival was significantly improved at both 30 days (74.3% vs. 45.7% for prednisone alone) and 90 days (68.6% vs. 20.0%).[35] A subsequent publication from the same trial confirmed improved survival at 3 and 6 months for patients receiving Metadoxine with either prednisone or pentoxifylline.[33]
• In addition to the primary survival endpoint, patients receiving Metadoxine experienced a lower incidence of severe complications, including the development or progression of hepatic encephalopathy and hepatorenal syndrome.[35] The study also found that patients treated with Metadoxine were more likely to maintain alcohol abstinence, which was identified as a key independent predictor of long-term survival.[33]

6.4 Alcohol Dependence and Craving

Beyond treating the physical consequences of alcohol use, there is preliminary evidence that Metadoxine may also aid in reducing alcohol consumption and craving, key components of alcohol dependence.

• A retrospective study by Leggio et al. (2011) analyzed 94 outpatients with alcohol dependence who were treated with Metadoxine (mean dose ~1300 mg/day).[36] The study found a significant decrease in the number of drinks consumed per week and in craving scores as measured by a Visual Analog Scale (VAS).
• This suggests a potential role for Metadoxine as a pharmacotherapy for alcohol dependence itself. This is particularly relevant for patients with co-existing severe liver disease, as standard treatments for alcohol dependence like naltrexone and acamprosate may be contraindicated in this population.[36]

Table 3: Summary of Key Clinical Trials of Metadoxine in Alcohol-Related Disorders

Indication	Study / Trial ID	Phase / Design	Patient Population (N)	Dosing Regimen	Key Efficacy Endpoints	Source(s)
Acute Alcohol Intoxication	Shpilenya et al., 2002	Randomized, Double-Blind, Placebo-Controlled	58	900 mg IV (single dose)	Reduced ethanol half-life; Faster time to recovery; Improved symptom scores.	28
Acute Alcohol Intoxication	Díaz Martínez et al., 2002	Randomized, Open-Label	52	300 mg IV (added to standard care)	Greater improvement in intoxication category; Greater decrease in blood alcohol concentration.	20
Alcoholic Fatty Liver	Caballería et al., 1998	Randomized, Double-Blind, Placebo-Controlled	136	1500 mg/day oral for 3 months	Accelerated normalization of liver function tests; Reduced steatosis on ultrasound; Efficacy in non-abstinent patients.	30
Severe Alcoholic Hepatitis	Higuera-de la Tijera et al. (NCT02161653)	Randomized, Open-Label	135	500 mg oral TID for 30 days (added to prednisone or pentoxifylline)	Improved 3- and 6-month survival; Reduced incidence of encephalopathy and hepatorenal syndrome; Increased alcohol abstinence.	[32, 33]
Alcohol Dependence	Leggio et al., 2011	Retrospective	94	500-2000 mg/day oral	Significant decrease in drinks per week; Significant reduction in craving (VAS).	36

7.0 Investigational Clinical Applications

Parallel to its established use in alcohol-related disorders, Metadoxine was the subject of an ambitious but ultimately unsuccessful development program aimed at repositioning it for several other conditions, most notably neurodevelopmental and metabolic disorders. This effort relied on an extended-release (ER) formulation designed to provide sustained drug exposure.

7.1 Attention-Deficit/Hyperactivity Disorder (ADHD)

The investigation of Metadoxine for ADHD, particularly the predominantly inattentive (PI) subtype, was based on its neuromodulatory mechanism of action, including its effects on the GABA and serotonin systems, and preclinical data suggesting cognitive-enhancing properties.[2]

• Early-Phase Success: Several Phase II studies of the ER formulation (MDX) yielded promising results, demonstrating what was described as a "consistent signal of efficacy" and "clinically meaningful improvements" in both clinical symptom scales (e.g., CAARS) and objective neuropsychological tests of attention (e.g., TOVA).[2] These positive findings were sufficient to justify advancing the program to a pivotal Phase III trial.
• Phase III Failure: The large-scale MEASURE study, a Phase III trial involving 300 adults with ADHD, was completed in 2014. In a significant setback for the program, the sponsor, Alcobra Ltd., announced in January 2017 that the trial had failed to meet its primary endpoints, showing no statistically significant advantage over placebo.[2]
• Regulatory Hurdles: The program's viability was further compromised by a clinical hold placed by the U.S. FDA. This action was not based on adverse events observed in human trials but stemmed from findings of potential neurotoxicity in long-term animal studies.[2] This created a major regulatory barrier that, combined with the lack of efficacy, effectively terminated the development of Metadoxine for ADHD.

7.2 Fragile X Syndrome (FXS)

The rationale for investigating Metadoxine in FXS, a genetic disorder that is a common cause of intellectual disability and autism, was strong. The pathophysiology of FXS involves impaired GABAergic neurotransmission, a system directly modulated by Metadoxine.[2]

• Preclinical Support: Studies in the Fmr1 knockout mouse model of FXS were encouraging. Metadoxine treatment was shown to improve behavioral deficits in learning, memory, and social interaction. It also reversed the overactivation of key intracellular signaling biomarkers (Akt and ERK) implicated in the disease and helped restore normal neuronal morphology.[2]
• Clinical Development and Designation: Based on this rationale, Metadoxine received Orphan Drug Designation for the treatment of FXS from both the U.S. FDA (2013) and the European Commission (2016).[39] A Phase II study in adolescents and adults with FXS was completed in 2015.[2] However, a related trial in patients with ADHD associated with FXS reportedly failed to meet its primary and secondary endpoints, dampening enthusiasm for this indication.[38]

7.3 Non-Alcoholic and Metabolic Dysfunction-Associated Steatohepatitis (NASH/MASH)

Given its known hepatoprotective properties and its mechanism of inhibiting adipogenesis, Metadoxine was also evaluated for the treatment of NASH (now more commonly referred to as MASH), a prevalent metabolic liver disease.

• Clinical Trial Results: A Phase II randomized, placebo-controlled trial (Shenoy et al., 2014) investigated Metadoxine (1000 mg/day) in 134 patients with biopsy-confirmed NASH over 16 weeks.[41] The results were largely negative. The study failed to show any significant difference between Metadoxine and placebo in terms of improving liver histology (the gold-standard endpoint for NASH) or in normalizing liver enzyme levels (ALT and AST). The only statistically significant finding was an improvement in the grade of steatosis as assessed by ultrasound, but this was not corroborated by the more definitive histological analysis. The authors concluded that Metadoxine was not effective for NASH at the dose and duration studied.[41] Other clinical trials for this indication have also been recorded as completed or withdrawn.[6]

The collective failure of Metadoxine to demonstrate robust efficacy in these large, well-controlled trials for ADHD and NASH, coupled with the emergence of a preclinical safety signal, stands in stark contrast to the positive evidence in alcohol-related disorders. This history serves as a case study in the challenges of drug repositioning, where a plausible mechanism of action and promising early-phase data do not guarantee success in late-stage development for complex, multifactorial diseases.

8.0 Safety and Tolerability Profile

8.1 Summary of Adverse Events from Clinical Trials

Across numerous clinical trials and decades of post-marketing surveillance, Metadoxine has generally been found to be safe and well-tolerated.[7] The adverse events (AEs) reported are typically mild to moderate in severity, transient, and rarely lead to treatment discontinuation.

• Common Adverse Events: The most consistently reported side effects are gastrointestinal in nature. These include:
• Nausea and vomiting [1]
• Diarrhea [1]
• Upset stomach, abdominal pain or distension, and flatulence [1]
• Decreased appetite [1]
• Other Reported Events: Less frequently, other systemic effects have been observed:
• Neurological: Drowsiness, dizziness, headache, and restlessness.[1]
• Dermatological: Skin rash and itching.[1]
• Cardiovascular: Tachycardia (fast heartbeat) has been reported.[3]
• Safety in Specific Trials:
• In the Phase II trial of extended-release Metadoxine for ADHD, the most frequent AEs were nausea (17% in the drug group vs. 0% in placebo), fatigue (31% vs. 27%), and headache (29% vs. 39%). The rates of fatigue and headache were comparable to placebo, suggesting a good overall tolerability profile.[5]
• In trials for severe alcoholic hepatitis and acute alcohol intoxication, no major adverse effects were attributed to Metadoxine therapy, with the incidence of gastrointestinal events being similar to the control groups.[29]
• Preclinical Toxicity Findings: A critical aspect of Metadoxine's safety profile is the discrepancy between its benign clinical record and a significant preclinical finding. The U.S. FDA placed a clinical hold on the ADHD development program due to observations of neurotoxicity in long-term animal (rat) studies.[2] This adverse finding was not observed in any of the human clinical trials. This divergence highlights a potential risk of cumulative toxicity with chronic, long-term exposure that may not be captured in shorter-term clinical studies and represents an unresolved safety concern that ultimately halted its development for chronic indications in the U.S.

8.2 Contraindications, Warnings, and Precautions

Based on its known properties and the available clinical data, several contraindications and warnings apply to the use of Metadoxine.

• Contraindications: The primary contraindication is a known history of hypersensitivity or allergy to Metadoxine or its components, pyridoxine and pidolic acid.[3]
• Pregnancy and Lactation: Metadoxine is generally not recommended for use during pregnancy or breastfeeding. Animal studies have indicated potential adverse effects on the fetus, and there is a lack of adequate human data to establish safety. Its use should be restricted to situations where the potential benefit to the mother is judged to outweigh the potential risk to the fetus or infant, and only under strict medical supervision.[1]
• Renal and Hepatic Impairment: Caution is advised when administering Metadoxine to patients with pre-existing kidney disease, and dose adjustments may be necessary.[43] The guidance for severe liver impairment is conflicting; while the drug is indicated for alcoholic liver disease, some sources advise against its use in severe liver impairment, likely reflecting a general precaution for any drug in patients with advanced hepatic dysfunction.[19]
• Effects on Alertness: As Metadoxine may cause dizziness or drowsiness in some individuals, patients should be cautioned against driving or operating heavy machinery until they are aware of how the medication affects them.[19]

8.3 Known and Potential Drug-Drug Interactions

The potential for drug-drug interactions with Metadoxine primarily stems from its pyridoxine (vitamin B6) component.

• Levodopa: This is the most well-documented interaction. Pyridoxine is a cofactor for the enzyme dopa decarboxylase, which peripherally metabolizes levodopa, a cornerstone therapy for Parkinson's disease. By enhancing this peripheral metabolism, pyridoxine can reduce the amount of levodopa that reaches the brain, thereby decreasing its therapeutic efficacy.[3] This interaction is less of a concern with modern levodopa formulations that are co-administered with a peripheral decarboxylase inhibitor (e.g., carbidopa).
• Anticonvulsants: The pyridoxine component may also alter the metabolism and efficacy of certain anticonvulsant drugs, such as phenobarbital and phenytoin.[25]
• Sedative Agents and Opioids: One source suggests a potential for interaction with sedative agents like benzodiazepines and opioids, although the mechanism and clinical significance of this are not well-defined.[19]
• Alcohol: The interaction with alcohol is complex. While Metadoxine is used to treat alcohol intoxication, one source warns that it may cause disulfiram-like reactions (e.g., flushing, tachycardia, nausea) when taken with alcohol.[1] Most sources, however, simply advise patients to avoid alcohol consumption while on treatment to avoid negating the therapeutic benefits and exacerbating liver damage.[43]

9.0 Global Regulatory Landscape

The regulatory status of Metadoxine is highly fragmented, reflecting its divergent development history and differing standards and priorities among global health authorities. It is an approved medicine for specific indications in some jurisdictions while remaining an unapproved, investigational agent in others.

9.1 United States (Food and Drug Administration - FDA)

In the United States, Metadoxine is not approved by the FDA for any therapeutic indication.[45] Its entire development history in the U.S. has been under an Investigational New Drug (IND) status.

• Investigational History: The sponsor Alcobra Ltd. pursued development for ADHD and Fragile X Syndrome.[45] However, this program was effectively terminated following the failure of the Phase III trial for ADHD and the imposition of a clinical hold by the FDA due to preclinical safety concerns.[2]
• Orphan Drug Designation: Despite the lack of approval, the FDA granted Metadoxine an Orphan Drug Designation on December 16, 2013, for the "Treatment of Fragile X Syndrome".[40] This designation provides development incentives but does not constitute marketing approval.

9.2 European Union (European Medicines Agency - EMA) and Member States

The regulatory picture in Europe is more complex. Metadoxine does not have a centralized marketing authorization from the European Medicines Agency (EMA), meaning it is not approved for use across the entire EU.[47]

• National Authorizations: The drug is approved via national procedures in several individual EU member states. The available information specifically identifies Hungary, Italy, Lithuania, and Portugal as countries where Metadoxine is authorized for the treatment of alcohol dependence, alcohol intoxication, and/or alcoholic fatty liver.[37] For example, the product is marketed in Italy under the trade name Metadoxil.[48] This reflects a long-standing acceptance of its risk-benefit profile for these specific indications within those countries.
• Orphan Designation: Similar to the U.S., the European Commission granted Metadoxine an orphan designation on June 27, 2016, for the "treatment of fragile X syndrome," based on a positive opinion from the Committee for Orphan Medicinal Products (COMP).[39]

9.3 Australia (Therapeutic Goods Administration - TGA)

Based on a thorough review of the provided materials and knowledge of the Australian regulatory system, Metadoxine is not approved for supply in Australia. It is not listed on the Australian Register of Therapeutic Goods (ARTG), which is the public database of all therapeutic goods that can be legally marketed in the country.[49] Any use of Metadoxine in Australia would have to occur under special access pathways, such as for clinical trials or through the personal importation scheme, but it does not have general marketing approval.

This divergent global status is a direct consequence of the drug's history. Its approval in some European nations is based on a legacy of use for alcohol-related conditions. In contrast, its failure to gain approval in the U.S. is a result of a modern, ambitious, and ultimately unsuccessful development program for different indications that was held to the rigorous efficacy and safety standards of the current regulatory era.

Table 4: Summary of Global Regulatory Status and Designations for Metadoxine

Regulatory Body	Approved Indications	Investigational Indications	Orphan Designations	Overall Status
U.S. FDA	None	ADHD, Fragile X Syndrome (Development Halted)	Fragile X Syndrome	Not Approved
EMA (Centralized)	None	Fragile X Syndrome	Fragile X Syndrome	Not Approved Centrally
National (e.g., Italy, Hungary)	Acute/Chronic Alcohol Intoxication, Alcoholic Liver Disease, Alcohol Dependence	N/A	N/A	Approved Nationally
Australia (TGA)	None	None	None	Not Approved

10.0 Expert Analysis and Future Directions

10.1 Synthesis of Evidence: A Drug with a Dichotomous Profile

The comprehensive body of evidence on Metadoxine paints a picture of a drug with a starkly dichotomous profile. On one hand, there is a consistent and compelling case for its utility as a niche therapeutic agent in the management of alcohol-related disorders. On the other hand, its history is defined by a high-profile failure to be repositioned as a treatment for complex neurodevelopmental and metabolic diseases.

The evidence supporting its use in alcoholism is robust and multifaceted. In acute alcohol intoxication, randomized controlled trials confirm that it accelerates ethanol clearance and improves clinical symptoms, offering a clear therapeutic benefit.[28] In chronic alcoholic liver disease, its value is even more pronounced. The trial by Caballería et al. (1998) stands out for demonstrating not only an improvement in liver function and a reduction in steatosis but also for showing efficacy in patients who were unable to maintain complete abstinence.[30] This finding is of profound clinical relevance, as it positions Metadoxine as a potential harm-reduction agent in a difficult-to-treat patient population. Furthermore, the striking survival benefit observed in patients with severe alcoholic hepatitis when Metadoxine was added to standard care suggests it could be a life-saving adjunct in this critical setting.[33]

Conversely, the attempt to pivot Metadoxine into the larger markets of ADHD and NASH was a clear failure. The program for ADHD and Fragile X Syndrome, despite a plausible biological rationale and promising early-phase data, could not demonstrate sufficient efficacy in a large Phase III trial.[2] The emergence of a preclinical neurotoxicity signal, which prompted an FDA clinical hold, created an insurmountable regulatory hurdle that underscored the risks of long-term administration.[38] Similarly, the drug failed to produce meaningful improvements in liver histology in patients with NASH, indicating that its hepatoprotective effects may be specific to the pathophysiology of alcohol-induced injury and not potent enough to reverse the complex metabolic inflammation of NASH.[41]

10.2 Unanswered Questions and Recommendations for Future Research

The existing data on Metadoxine, while strong in some areas, is marked by significant gaps. A targeted research agenda could solidify its clinical role and resolve outstanding questions.

1. Definitive Pharmacokinetic Characterization: The most critical need is for a comprehensive Phase I study to fully characterize the oral pharmacokinetics of Metadoxine. This study should determine its absolute oral bioavailability, the effect of food on its absorption, its full metabolic profile (confirming the fate of the dissociated pyridoxine and PCA components), and a complete mass balance analysis to identify all routes of excretion. Without this foundational data, optimal dosing for chronic conditions remains speculative.
2. Elucidation of Mechanism of Action: Further research is warranted to resolve the conflicting reports regarding Metadoxine's effect on alcohol dehydrogenase activity. Quantifying the relative contributions of its direct metabolic enhancement (accelerated ethanol/acetaldehyde clearance) versus its neuromodulatory effects (e.g., GABAergic modulation) to the rapid improvement of symptoms in acute intoxication would provide a more nuanced understanding of its action.
3. Confirmatory Trial in Severe Alcoholic Hepatitis (SAH): The survival benefit shown in SAH is perhaps the most significant clinical finding for Metadoxine. However, the evidence comes from open-label trials. A large, multi-center, double-blind, placebo-controlled trial is needed to definitively confirm this life-saving effect and potentially establish Metadoxine as a standard of care in this patient population.
4. Harm Reduction in Alcoholic Liver Disease: The finding that Metadoxine benefits patients with alcoholic fatty liver even with ongoing alcohol consumption is unique. Future clinical trials should be designed specifically to explore this harm-reduction potential. Such a study could evaluate long-term outcomes (e.g., progression to fibrosis or cirrhosis) in patients with ongoing alcohol use disorder treated with Metadoxine versus placebo.

10.3 Concluding Assessment of Metadoxine's Therapeutic Potential

In conclusion, Metadoxine is a valuable therapeutic agent whose true potential has been obscured by an unsuccessful and strategically ambitious repositioning effort. The evidence strongly supports its efficacy and safety for the treatment of acute alcohol intoxication, alcoholic fatty liver disease, and as an adjunctive therapy in severe alcoholic hepatitis. Its unique ability to mitigate liver damage in non-abstinent patients and to improve survival in severe disease constitutes its most significant contribution to clinical medicine.

The failure of the extended-release formulation in ADHD and NASH should not detract from the drug's proven utility in its original indications. Instead, it serves as a cautionary example of the immense challenges in drug development, where a plausible mechanism and early promise do not guarantee late-stage success, and where unforeseen preclinical safety signals can derail even the most advanced programs.

The future of Metadoxine does not lie in pursuing broad, blockbuster markets. Rather, its path forward should focus on solidifying the evidence base within its core area of expertise: the multifaceted management of alcohol toxicity. For clinicians in the jurisdictions where it is approved, it remains a vital tool. For the global medical community, a renewed focus on rigorous, confirmatory trials in severe alcoholic hepatitis and on its potential as a harm-reduction agent could firmly establish its place as a unique and important medicine in the fight against alcohol-related disease.

Works cited

1. Metadoxine - Uses, Side Effects, Substitutes, Composition And More | Lybrate, accessed October 31, 2025, https://www.lybrate.com/medicine/metadoxine
2. Metadoxine - Wikipedia, accessed October 31, 2025, https://en.wikipedia.org/wiki/Metadoxine
3. Metadoxine - Uses, Dosage, Side Effects, Price, Composition | Practo, accessed October 31, 2025, https://www.practo.com/medicine-info/metadoxine-1649-api
4. metadoxine - New Drug Approvals, accessed October 31, 2025, https://newdrugapprovals.org/tag/metadoxine/
5. A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Evaluating the Efficacy, Safety, and Tolerability of Extended-Release Metadoxine in Adults With Attention-Deficit/Hyperactivity Disorder - Psychiatrist.com, accessed October 31, 2025, https://www.psychiatrist.com/jcp/randomized-double-blind-placebo-controlled-multicenter/
6. Metadoxine: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed October 31, 2025, https://go.drugbank.com/drugs/DB16554
7. (PDF) Pharmacology, Systematic Review and Recent Clinical Trials of Metadoxine, accessed October 31, 2025, https://www.researchgate.net/publication/323436100_Pharmacology_Systematic_Review_and_Recent_Clinical_Trials_of_Metadoxine
8. (PDF) Metadoxine regulation of elimination of ethanol and its metabolites from the rat's body, accessed October 31, 2025, https://www.researchgate.net/publication/321766004_Metadoxine_regulation_of_elimination_of_ethanol_and_its_metabolites_from_the_rat's_body
9. The beneficial effect of metadoxine (Pyridoxine ... - AKJournals, accessed October 31, 2025, https://akjournals.com/downloadpdf/journals/1526/3/1/article-p65.pdf
10. Metadoxine | C13H18N2O6 | CID 115198 - PubChem - NIH, accessed October 31, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Metadoxine
11. Metadoxine | 5-HT Receptor antagonist | Mechanism | Concentration - Selleck Chemicals, accessed October 31, 2025, https://www.selleckchem.com/products/metadoxine.html
12. CAS 74536-44-0 Metadoxine - Alfa Chemistry, accessed October 31, 2025, https://www.alfa-chemistry.com/metadoxine-cas-74536-44-0-item-293528.htm
13. Metadoxine | CAS 74536-44-0 | SCBT - Santa Cruz Biotechnology, accessed October 31, 2025, https://www.scbt.com/p/metadoxine-74536-44-0
14. Metadoxine | 74536-44-0 - ChemicalBook, accessed October 31, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4837260.htm
15. KEGG DRUG: Metadoxine, accessed October 31, 2025, https://www.genome.jp/dbget-bin/www_bget?dr:D08186
16. Metadoxine | CAS NO.:74536-44-0 - GlpBio, accessed October 31, 2025, https://www.glpbio.com/metadoxine.html
17. Metadoxine | PKA Inhibitor - MedchemExpress.com, accessed October 31, 2025, https://www.medchemexpress.com/Metadoxine.html
18. Metadoxine: View Uses, Side Effects and Medicines - Truemeds, accessed October 31, 2025, https://www.truemeds.in/drug-salts/metadoxine-6248
19. Efficacy of metadoxine in the management of acute alcohol intoxication - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/11921498/
20. NCT02189772 | Safety and Tolerability Study of Metadoxine Extended Release (MDX) (Previously Known as MG01CI) in PI-ADHD Adolescent Subjects | ClinicalTrials.gov, accessed October 31, 2025, https://www.clinicaltrials.gov/study/NCT02189772
21. Metadoxine prevents damage produced by ethanol and acetaldehyde in hepatocyte and hepatic stellate cells in culture - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/11712874/
22. www.mims.com, accessed October 31, 2025, https://www.mims.com/singapore/drug/info/metadoxine?mtype=generic#:~:text=Mechanism%20of%20Action%3A%20Metadoxine%20enhances,to%20prevent%20TNF%2D%CE%B1%20induction.
23. Pharmacokinetics and Tolerability of Intravenous Metadoxine in ..., accessed October 31, 2025, http://www.latamjpharm.org/resumenes/37/7/LAJOP_37_7_1_17.pdf
24. What is Metadoxine used for? - Patsnap Synapse, accessed October 31, 2025, https://synapse.patsnap.com/article/what-is-metadoxine-used-for
25. Metadoxine regulation of elimination of ethanol and its metabolites from the rat's body, accessed October 31, 2025, http://cphj.nuph.edu.ua/article/view/cphj.16.1382
26. Pharmacokinetics of metadoxine for inj ection after repeated doses - MedNexus, accessed October 31, 2025, https://mednexus.org/doi/pdf/10.5555/cmj.0366-6999.120.02.p166.01
27. Metadoxine in Acute Alcohol Intoxication: A Double-Blind ..., accessed October 31, 2025, https://www.researchgate.net/publication/11440883_Metadoxine_in_Acute_Alcohol_Intoxication_A_Double-Blind_Randomized_Placebo-Controlled_Study
28. Efficacy of Metadoxine in the Management of Acute Alcohol Intoxication - ResearchGate, accessed October 31, 2025, https://www.researchgate.net/publication/11442726_Efficacy_of_Metadoxine_in_the_Management_of_Acute_Alcohol_Intoxication
29. Metadoxine accelerates fatty liver recovery in alcoholic patients: results of a randomized double-blind, placebo-control trial. Spanish Group for the Study of Alcoholic Fatty Liver - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/9537864/
30. Treatment with Metadoxine and its impact on early mortality in patients with severe alcoholic hepatitis | Annals of Hepatology - Elsevier, accessed October 31, 2025, https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-treatment-with-metadoxine-its-impact-S1665268119308634
31. Study Details | NCT02161653 | Metadoxine as a Therapy for Severe Alcoholic Hepatitis, accessed October 31, 2025, https://clinicaltrials.gov/study/NCT02161653
32. Metadoxine improves the three- and six-month survival rates in patients with severe alcoholic hepatitis - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/25945012/
33. Metadoxine improves the three- and six-month survival rates in patients with severe alcoholic hepatitis - PubMed Central, accessed October 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4408471/
34. (PDF) Treatment with metadoxine and its impact on early mortality in ..., accessed October 31, 2025, https://www.researchgate.net/publication/261801497_Treatment_with_metadoxine_and_its_impact_on_early_mortality_in_patients_with_severe_alcoholic_Hepatitis
35. Preliminary findings on the use of metadoxine for the treatment of alcohol dependence and alcoholic liver disease | Request PDF - ResearchGate, accessed October 31, 2025, https://www.researchgate.net/publication/51807988_Preliminary_findings_on_the_use_of_metadoxine_for_the_treatment_of_alcohol_dependence_and_alcoholic_liver_disease
36. Preliminary findings on the use of metadoxine for the treatment of alcohol dependence and alcoholic liver disease - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/22095793/
37. FDA halts trial of Alcobra's ADHD drug - BioPharma Dive, accessed October 31, 2025, https://www.biopharmadive.com/news/fda-alcobra-clinical-hold-adhd/427368/
38. EU/3/16/1673 - orphan designation for treatment of fragile X syndrome | European Medicines Agency (EMA), accessed October 31, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-16-1673
39. Search Orphan Drug Designations and Approvals - FDA, accessed October 31, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=414513
40. Metadoxine Versus Placebo for the Treatment of Non-alcoholic Steatohepatitis: A Randomized Controlled Trial - PubMed Central, accessed October 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4116708/
41. Metadoxine in the treatment of acute and chronic alcoholism: a review - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/14611722/
42. Metadoxine: Uses, Side Effects and Medicines | Apollo Pharmacy, accessed October 31, 2025, https://www.apollopharmacy.in/salt/Metadoxine
43. What are the side effects of Metadoxine? - Patsnap Synapse, accessed October 31, 2025, https://synapse.patsnap.com/article/what-are-the-side-effects-of-metadoxine
44. Metadoxine: What is it and is it FDA approved? - Drugs.com, accessed October 31, 2025, https://www.drugs.com/history/metadoxine.html
45. FDA approves Alcobra's protocol for Phase IIb study of metadoxine drug candidate, accessed October 31, 2025, https://newdrugapprovals.org/2014/06/30/fda-approves-alcobras-protocol-for-phase-iib-study-of-metadoxine-drug-candidate/
46. European Medicines Agency (EMA), accessed October 31, 2025, https://www.ema.europa.eu/en/medicines
47. US20120029031A1 - Metadoxine for use as inhibitor of hepatic fibrosis - Google Patents, accessed October 31, 2025, https://patents.google.com/patent/US20120029031A1/en
48. Australian Register of Therapeutic Goods (ARTG), accessed October 31, 2025, https://www.tga.gov.au/products/australian-register-therapeutic-goods-artg
49. What does TGA approval of medicines mean? - Australian Prescriber, accessed October 31, 2025, https://australianprescriber.tg.org.au/articles/what-does-tga-approval-of-medicines-mean.html