Pangamic acid

Synopsis

Pangamic Acid (Vitamin B15)

1. Identity: Nomenclature, Chemistry, and Forms

1.1 Names and Designations

Pangamic acid, also called pangamate, is the name given to a chemical compound discovered by Ernst T. Krebs Sr., whose son, Ernst T. Krebs Jr., promoted it as a medicinal compound for use in treatment of a wide range of diseases. They also termed this chemical "vitamin B15," though it is not a true vitamin, has no nutritional value, has no known use in the treatment of any disease, and has been called a "quack remedy."

Other synonyms and trade-related names encountered in the literature include: pangamate, calcium pangamate, vitamin B-15, vitamine B15, acide pangamique, ácido pangámico, and Calgam. The substance is also referenced by the trade designations diisopropylamine dichloroacetate and calcium pangamate.

1.2 Claimed Chemical Identity

Pangamic acid is the name given to the chemical compound with the empirical formula C₁₀H₁₉O₈N and a molecular weight of 281, which appeared to be an ester derived from d-gluconic acid and dimethylglycine. In 1943, the Krebses applied for a patent for a process for extracting this chemical compound, which they reported had been previously isolated from apricot seeds, and received the patent in 1949 (US2464240). A 1951 paper by the Krebses reported the first isolation of this compound using this patented process, but did not include enough information to confirm that this compound was actually isolated.

Crucially, the chemical identity of pangamic acid has never been established with scientific rigor. Subsequent attempts at synthesizing this ester by other researchers found Krebs' purported methods of producing pangamic acid were not reproducible, and research into pangamic acid has focused on compounds of various chemical compositions. A review noted that of all the chemicals described in research about pangamic acid, "not a single product labeled 'pangamate' or 'B15' has been established in a scientifically verifiable manner to conform to the empiric formula" described by the Krebses.

Analysis of a sample of a compound called "pangamic acid" which was provided by a co-worker of the Krebses in the 1950s showed only lactose upon further evaluation by nuclear magnetic resonance spectroscopy. The chemical identity of genuine vitamin B15 (pangamic acid) has apparently never been ascertained or verifiably chemically identified as being the molecular weight 281-ester of DMG and gluconic acid claimed by Krebs and some Russian authors, and there is considerable doubt that such a stable substance exists with the straight chain sugar gluconic acid.

1.3 Compounds Sold Under the Pangamic Acid Label

Because no single, verified chemical entity exists, the term "pangamic acid" has been applied to a variety of substances over time. Substances that have been claimed to be pangamic acid include d-gluconodimethylamino acetic acid (Krebs 1951), which was never synthesized. Diisopropylamine dichloroacetate (a 1955 Krebs patent "analogue") was synthesized but readily hydrolyzes to known-toxic compounds. Pharmacologically inert materials, ranging from "synthesis attempts" containing calcium gluconate to pure lactose, have also been sold under the pangamic acid label.

There is no standard chemical identity for pangamic acid. Formulations can include one or more of the following: sodium gluconate, calcium gluconate, glycine, diisopropylamine dichloroacetate, dimethylglycine, calcium chloride, dicalcium phosphate, stearic acid, cellulose, or other chemical compounds.

1.4 Naming Etymology

The Krebses derived the term "pangamic" to describe this compound, which they asserted to be ubiquitous and highly concentrated in seeds (pan meaning "universal" and gamic meaning "seed").

1.5 Natural Sources

Pangamic acid was first isolated from aqueous extracts of kernels from apricot stones, and later it was crystallized from rice shoots, rice bran, brewer's yeast, bull blood, and horse liver. Natural sources for D-gluconodimethyl aminoacetic acid include brewer's yeast, whole brown rice, sesame seeds, and pumpkin seeds. Pangamic acid is the name given to a product originally claimed to contain D-gluconodimethyl aminoacetic acid, which was obtained from apricot kernels and later from rice bran.

1.6 Common Preparations and Dosage Forms

Commercial preparations of pangamic acid have been marketed in tablet and powder forms. One controlled study examined the effect of pangamic acid formulated as calcium gluconate and N,N-dimethylglycine; the experimental group ingested six 50-mg pangamic acid tablets per day for three weeks. The typical dose cited in older literature is 50 to 150 mg per day. Because pangamic acid is a term used for many different chemicals, there is not enough reliable information to know what an appropriate dose might be.

2. Historical and Traditional Use

2.1 Discovery and Early Promotion (1940s–1950s, United States)

Ernst Krebs Sr. and Jr. isolated a material from apricot kernels in 1943 and named it "pangamic acid." It was then trade-named "vitamin B-15," although according to the Food and Drug Administration it is an untested food additive, not a vitamin, nor does it have any medical or nutritional usefulness.

The Krebses' original patent claimed pangamic acid could be used for detoxification as well as treatment of asthma, skin conditions, joint pain, and nerve pain, with none of these claims supported by evidence in the patent application. Early promotion for pangamic acid included use by race horses as well as humans.

Krebs Jr. promoted pangamic acid as "vitamin B15," claiming it functioned as an essential nutrient involved in methylation processes and energy metabolism. This promotion drew from initial observations in animal experiments, where the substance appeared to enhance oxygen utilization and tissue respiration, leading to early misconceptions that it was a true vitamin despite lacking evidence of deficiency diseases or specific physiological requirements.

2.2 Soviet Union Research and Application (1960s–1980s)

In the Soviet Union during the early 1960s, researchers built upon early findings with enthusiastic investigation, conducting pioneering studies on its isolation from additional plant materials and its potential roles in oxidative metabolism.

The former Soviet Union had been the most enthusiastic about pangamic acid, feeling that it is a very important nutrient with physiological actions that can treat a multitude of symptoms and diseases. It had been used regularly and commonly in the Soviet Union for many problems, including alcoholism and drug addiction; mental problems such as those of aging and senility, minimal brain damage in children, autism, and schizophrenia; heart disease and high blood pressure; diabetes; skin diseases; liver disease; and chemical poisonings.

Russian researchers in the 1960s expanded on these claims through animal and limited human studies, reporting benefits such as improved endurance, reduced lactic acid buildup during exercise, and protection against hypoxia and toxins, often using calcium pangamate formulations.

Much of the clinical research on pangamic acid took place in the former Soviet Union, though that research often did not describe which of the many compounds called "pangamic acid" was used in the study. This research was also of limited quality due to being overwhelmingly anecdotal in nature (as opposed to controlled experimentation) and ignoring short and long term safety in human use.

2.3 Spread to Western Markets and Athletes (1970s–1980s)

A substance labeled pangamic acid or vitamin B15 was extensively used as a performance enhancer by Russian athletes and became popular among American athletes. Pangamic acid was initially brought into the American nutritional market based on studies undertaken by Soviet sports scientists. Little to no research has been conducted in the United States.

Despite the lack of evidence, pangamic acid was advertised as a cure for many ills, ranging from eczema to cancer, and was sold in many health food stores.

3. Key Constituents and Proposed Mechanisms of Action

3.1 Dimethylglycine (DMG)

Research over the years gave evidence that the biological activity ascribed to pangamate B15 was in fact due to DMG. DMG is an active amino acid and intermediate metabolite in the one-carbon choline cycle. Its primary function is to contribute methyl groups for the methylation reactions and provide other essential building blocks.

N,N-dimethylglycine (DMG) is an N-methylated derivative of the amino acid glycine. Researchers discovered DMG in 1943 as part of the pangamic acid (vitamin B15) structure. It is not a true vitamin, as the body can synthesize it in the citric acid cycle. DMG can also form by dropping one of the methyl groups from trimethylglycine (TMG) or as a byproduct during choline metabolism.

3.2 Proposed Mechanisms: Oxygen Utilization and Energy Metabolism

Initial observations in animal experiments showed the substance appeared to enhance oxygen utilization and tissue respiration. Soviet-era proponents claimed that pangamic acid acted as a lipotropic agent (facilitating fat metabolism), a methyl donor supporting transmethylation reactions, and an agent that improved cellular respiration under hypoxic conditions. Since there is no standard identity for the chemicals in pangamic acid, how it might work is unknown.

3.3 Methylation Pathway

The most scientifically defensible proposed mechanism relates to the DMG component's role as a methyl donor. Research over the years gave evidence that the biological activity ascribed to pangamate B15 was in fact due to DMG. DMG is an active amino acid and intermediate metabolite in the one-carbon choline cycle. Its primary function is to contribute methyl groups for the methylation reactions and provide other essential building blocks. Methylation reactions are involved in the biosynthesis of nucleic acids, phospholipids, epinephrine, and other biologically critical molecules, though no human clinical evidence has demonstrated that oral pangamic acid or its DMG component meaningfully upregulates these pathways in healthy individuals.

3.4 Lactic Acid Buffering

Pangamic acid (B15), a mixture of calcium gluconate and N,N-dimethylglycine (DMG), is widely used by amateur and professional athletes because they believe it lowers blood lactic acid, stabilizes blood sugar during exercise, and reduces the effects of fatigue. In general, Russian studies report increased oxygen efficiency, but they are not properly controlled. Some American studies support the claims of reduced lactic acid and increased performance, but others show no measurable effects.

3.5 Absence of Verified Mechanism

Since there is no standard identity for the chemicals in pangamic acid, how it might work is unknown. Although pangamic acid is also called vitamin B15, there is no research that shows it is required by the body, as the term "vitamin" would suggest. Evaluations highlighted the absence of a defined chemical identity and suitable analytical methods, rendering claims of efficacy unverifiable.

4. Scientific Evidence by Area of Use

The following sections summarize the available human and clinical evidence. Because "pangamic acid" has no consistent chemical definition, most studies employed preparations of variable composition; this is a fundamental limitation that applies to all research in this field.

4.1 Athletic Performance and Exercise Endurance

This area attracted the most formal investigation in the Western scientific literature, particularly from the late 1970s through the 1980s.

Study 1 (Gray & Titlow, 1982 — published in Medicine and Science in Sports and Exercise): The effect of pangamic acid (calcium gluconate and N,N-dimethylglycine) ingestion was examined during short-term maximal treadmill performance on 16 male track athletes. The study was conducted as a double-blind experiment with an experimental group whose members each ingested six 50-mg pangamic acid tablets per day and a control group whose members each ingested six placebo tablets per day for three weeks. The placebo tablets were identical to the pangamic acid tablets in appearance. Subjects were tested by using the Bruce treadmill protocol before and after treatment. Parameters examined included maximal heart rate, treadmill time, recovery heart rate at minutes 1 and 3, and pre- and post-test blood glucose and lactate levels. Gray and Titlow reported no significant changes in short-term maximal treadmill performance between the group receiving pangamic acid (calcium gluconate and N,N-dimethylglycine) and control.

Study 2 (Pipes, 1980 — reported in Medicine & Science in Sports and Exercise): In trained athletes, Pipes noted a 23.6% increase in time to fatigue after DMG supplementation. However, this result was not replicated in subsequent controlled work. Pipes, of the Institute of Human Fitness in Escondido, California, was among the first to study the effects of DMG on athletic performance. His first test was a one-week double-blind comparison of 5 mg daily DMG with placebo in 12 male college track athletes.

Additional Studies: No improvements in aerobic and anaerobic performance were reported when 400 mg of DMG per kg of body weight was administered to elite basketball players. DMG also failed to improve maximal treadmill exercise to exhaustion in well-trained college women. The authors of that study concluded that there is no evidence to recommend DMG as an ergogenic aid to endurance athletes.

Overall Evidence Quality: Dimethylglycine supplementation seems to have little to no effect on athletic performance; the available evidence is limited and conflicting. One small study failed to find this form of pangamic acid effective for enhancing sports performance. The evidence is characterized overall as weak, inconsistent, and derived from small, methodologically limited trials. No large, well-powered randomized controlled trials have been conducted.

4.2 Cardiovascular Disease

Early interest in pangamic acid's cardiovascular applications arose in the 1950s. A preliminary report of ten cases, published in the Journal of the American Osteopathic Association in 1952, described pangamic acid in the context of heart disease, but no abstract is available and the study design was not controlled. Soviet-era research reported that pangamic acid improved oxygen delivery to myocardial tissue and supported transmethylation in cardiopathies, but much of the clinical research on pangamic acid took place in the former Soviet Union, and that research often did not describe which of the many compounds called "pangamic acid" was used in the study; this research was also of limited quality due to being overwhelmingly anecdotal in nature and ignoring short and long-term safety in human use.

Although more recent claims include treatment of a wide variety of conditions including cancer, heart disease, schizophrenia as well as providing improvement in oxygen utilization, there is no significant evidence for any of these claims or that it is safe for human use. The cardiovascular evidence base consists entirely of early, uncontrolled case reports and Soviet-era observational data, and cannot be considered scientifically credible by modern standards.

4.3 Liver Disease

Pangamic acid has been investigated as a hepatoprotective agent. A 1957 publication in Minerva Medica titled "Pangamic acid in human therapy; pangamic acid and chronic liver diseases" (Vailati G, Invernizzi G) examined hepatic applications, though no abstract is available and the study lacked a modern controlled design. Soviet literature documented its use for chemical poisoning and liver-toxic conditions, but these reports were largely anecdotal. No peer-reviewed, controlled clinical trials have established benefit for liver disease.

4.4 Alcoholism and Substance Dependence

In Russia, a major claimed use of pangamic acid was for treating individuals with alcohol problems, possibly by reducing craving. It has been reported to diminish hangover symptoms when alcohol has been abused. These reports originate almost entirely from Soviet-era uncontrolled observations. No rigorous clinical trials have evaluated pangamic acid for alcoholism or substance dependence in modern controlled settings.

4.5 Neurological and Psychiatric Conditions (Autism, Schizophrenia)

The dimethylglycine (DMG) component of some pangamic acid formulations has been studied separately, particularly for autism spectrum disorders, but results are mixed. A double-blind, placebo-controlled, crossover pilot trial of low-dose dimethylglycine in patients with autistic disorder was conducted (Bolman WM, Richmond JA, Journal of Autism and Developmental Disorders, 1999). A subsequent investigation (Kern JK et al., Journal of Child Neurology, 2001) examined DMG in autism and pervasive developmental disorder. These studies represent the highest-quality research on DMG in a clinical neuropsychiatric population, though their results were mixed and the sample sizes were small.

Claims of benefit for schizophrenia and aging-related cognitive decline originate from the Soviet-era literature and are anecdotal in nature. There is no significant evidence for any of these claims or that pangamic acid is safe for human use.

4.6 Lipid Metabolism and Cholesterol

Soviet investigators documented studies on pangamic acid's use in hyperlipidemia. A 1976 PubMed-indexed study (PMID 1272928) was titled "Use of pangamic acid in hyperlipidemia," though no abstract is available in English. Addition of vitamin B15 (pangamic acid) to the diet of Wistar rats at 2.5 mg/100 g of diet increases the degree of fatty infiltration of the liver, which is maintained at a stable level throughout the whole experiment of 12–18 months. This animal finding raises concerns rather than supporting a lipid-lowering benefit. No rigorous human clinical trials have established pangamic acid as a lipid-lowering agent.

4.7 Skin Conditions (Eczema, Psoriasis)

Pangamic acid has been advertised as a treatment for eczema, among other conditions. A 1962 Spanish publication titled "Psoriasis and pangamic acid (vitamin B-15)" (Revista Clinica Española) examined dermatological applications, but no modern controlled evidence exists. More evidence is needed to rate the effectiveness of pangamic acid for skin conditions.

4.8 Cancer

Disputed claims have been made for pangamic acid's usefulness in the treatment of cancer, among other conditions. There is no significant evidence for the claim that pangamic acid treats cancer, and, paradoxically, the mutagenicity data on certain formulations suggests that some preparations may carry carcinogenic risk rather than anti-cancer benefit (see Section 6 below).

5. Body Systems and Health Areas of Association

The following body systems and health areas have been associated with pangamic acid in historical literature, traditional use, or research. This is a descriptive enumeration; it does not imply established efficacy.

Musculoskeletal / Exercise Physiology: Claimed to improve oxygen delivery to working muscles, reduce lactic acid accumulation, and extend time to fatigue.
Cardiovascular System: Claimed to improve myocardial oxygenation and support cardiac function through transmethylation.
Hepatic System: Claimed lipotropic and hepatoprotective effects; investigated in chronic liver disease.
Central Nervous System: Claimed to improve cerebral oxygenation; used in Soviet practice for autism, schizophrenia, aging-related cognitive decline, and senility.
Respiratory System: Claimed to benefit asthma and other pulmonary conditions.
Integumentary System: Claimed benefits for eczema, psoriasis, and other skin conditions.
Metabolic / Endocrine: Claimed benefits for diabetes and lipid metabolism (hyperlipidemia).
Detoxification / Toxicology: Claimed to assist in clearance of chemical poisonings and reduce effects of alcohol.
Immune System: The DMG component has been studied for immunomodulating properties in human subjects.

Despite serious safety concerns, pangamic acid has been used for improving exercise endurance; treating asthma and related diseases, skin conditions including eczema, lung problems, painful nerve and joint conditions, cancer, and arthritis; improving the oxygenation of the heart, brain, and other vital organs; and "detoxifying" the body. None of these uses is supported by high-quality clinical evidence.

6. Safety Considerations

6.1 Fundamental Safety Problem: Unknown Chemical Identity

Commercial preparations sold under the pangamic acid name are chemically inconsistent and often contain substances with potential toxicity. Because the formulation varies widely by manufacturer and era, safety cannot be characterized for "pangamic acid" as a single entity.

6.2 Mutagenicity of Common Formulation Ingredients

Diisopropylamine dichloroacetate, the active component of many formulations of pangamic acid (trade-named "vitamin B15"), and diisopropylamine, a component of diisopropylamine dichloroacetate, both demonstrate mutagenicity in the Ames Salmonella/mammalian microsome mutagenicity test. Ninety percent of such agents prove carcinogenic, and this long-term possibility must be considered in any proposed use of pangamic acid containing diisopropylamine or diisopropylamine dichloroacetate.

Dichloroacetate demonstrates low-grade mutagenicity in the Ames Salmonella/mammalian microsome mutagenicity test. This evidence of probable carcinogenicity must be considered in any proposed use of dichloroacetate or of preparations of pangamic acid containing dichloroacetate.

Mixtures of DMG with sodium nitrite have also shown mutagenicity in the Ames test, raising concerns about the formation of carcinogenic nitrosamines.

Positive results from mutagenicity analysis via the Ames test of compounds commonly found in preparations labelled "pangamic acid" — including diisopropylamine dichloroacetate, diisopropylamine, dichloroacetate, as well as dimethylglycine mixed with sodium nitrite — suggest there may be concern for the development of cancer with the use of these substances.

6.3 Animal Toxicology

Chronic exposure in rodents showed no direct carcinogenicity, though some components like diisopropylamine dichloroacetate exhibited mutagenic potential in vitro, and metabolic disruptions such as altered gluconeogenesis were observed.

6.4 Renal Considerations

Pangamic acid can cause kidney stones and other kidney problems, making existing kidney disease worse. Pangamic acid is contraindicated for individuals with kidney impairment due to its calcium content, which could worsen renal function or contribute to stone formation in vulnerable populations.

6.5 Pregnancy and Lactation

It is possibly unsafe to use pangamic acid while pregnant or breastfeeding. Chemicals found in some pangamic acid formulations can cause birth defects and/or cancer.

6.6 Gastrointestinal Effects

There are no widely documented harmful effects of pangamic acid from oral intake, but some users may initially suffer nausea.

7. Regulatory Status

7.1 United States

In the United States, the Food and Drug Administration (FDA) initiated regulatory actions, including seizures, against pangamic acid in 1971, classifying it as an unapproved new drug lacking a new drug application under the Federal Food, Drug, and Cosmetic Act. The agency considers it unsafe for food or drug use due to the absence of established chemical identity, nutritional properties, or analytical methods, recommending seizures and injunctions against products promoted for disease treatment.

The FDA has recommended seizing any chemicals advertised as pangamic acid and restraining the importation and interstate shipment of pangamic acid on the grounds that pangamic acid and pangamic acid products are unsafe for use and have no known nutritional properties.

The regulatory action criteria do not apply to dimethylglycine, when labeled as such and offered as a single ingredient compound for food use only. This distinction allows DMG—the component most plausibly responsible for any biological activity attributed to pangamic acid—to be sold as a separate dietary supplement in the United States.

FDA studies of various commercial products claiming to include vitamin B15 revealed that many had no pangamic acid. Pangamic acid was effectively restricted in the 1970s due to untested claims and rising safety concerns.

7.2 Canada

Pangamic acid's distribution in Canada has been prohibited by the then-named Canadian Food and Drug Directorate.

7.3 Russia and Europe

Vitamin B15 is available as calcium pangamate in several regions, including Russia and Europe. The substance was more widely used in Soviet-era clinical medicine and continues to have limited availability in some Eastern European markets.

8. Critical Assessment of the Evidence Base

The product has no standard of identity and its chemical composition varies. The pharmacology and clinical use of pangamic acid have been reviewed and support the conclusion that the product is a quack remedy.

One review noted that pangamic acid meets "the criteria that define a quack remedy."

In the 1970s, the U.S. Food and Drug Administration (FDA) commissioned reviews that concluded there was no accepted scientific evidence supporting pangamic acid's nutritional properties or identifying any deficiency states in humans or animals.

The fundamental problem obstructing any scientific evaluation of pangamic acid is not merely a lack of human trials; it is the prior and unresolved question of what substance is actually being studied. Although a number of compounds labelled "pangamic acid" have been studied or sold, no chemical compound, including those claimed by the Krebses to be pangamic acid, has been scientifically verified to have the characteristics that defined the original description of the compound. As a consequence, findings from one preparation cannot be generalized to another, making any cross-study synthesis impossible.

The DMG component, which has been studied in isolation, represents a more coherent scientific question. Evidence from human studies of DMG in sports performance is consistently negative in better-controlled trials, and evidence from autism studies is mixed. No systematic review or meta-analysis has concluded in favor of efficacy for any health claim associated with either pangamic acid or DMG used as a pangamic acid proxy.