IngredientsThe term hydrogen sulfate (chemical formula HSO4−, also called bisulfate) refers strictly to the conjugate base of sulfuric acid and has no established literature as a dietary supplement or physiologically active gaseous signaling compound. The biologically active, endogenously produced sulfur gas that is the subject of a large and growing body of peer-reviewed research — and whose precursors and donors are investigated as dietary supplements and therapeutic agents — is hydrogen sulfide (H2S). This article covers hydrogen sulfide in its roles as an endogenous gasotransmitter, its dietary and natural sources, the compounds used to boost or donate H2S in the body, and the scientific and traditional evidence for its health relevance.
Hydrogen sulfide (systematic name: sulfane; also dihydrogen monosulfide, hydrogen monosulfide) has the molecular formula H2S and a molecular weight of 34.08 g/mol. It is a sulfur analog of water and, due to its weak intermolecular force, exists in a gaseous form that is colorless but has an offensive odor. Hydrogen sulfide (H2S) is a colorless, flammable gas with a "rotten egg" smell.
At a pH of 7.4 in the mammalian body, one-fifth of the total H2S subsists in an undissociated form, with the remaining content existing as hydrosulfide anions (HS−) and sulfide (S2−). The high lipid solubility of H2S allows it to easily penetrate the plasma membrane of cells in its undissociated form, but it remains unclear whether this undissociated form is physiologically pertinent.
Over the last two decades, hydrogen sulfide (H2S) has emerged as an endogenous regulator of a broad range of physiological functions. H2S belongs to the class of molecules known as gasotransmitters, which typically include nitric oxide (NO) and carbon monoxide (CO). Gasotransmitters are small molecules of endogenous gases with important physiological functions. Their production and metabolism are enzymatically regulated, and their effects are not dependent on specific membrane receptors. Following the identification of nitric oxide and carbon monoxide as gasotransmitters, hydrogen sulfide (H2S) may be qualified as the third gasotransmitter.
In the past, hydrogen sulfide (H2S) was recognized as a toxic and dangerous gas; in recent years, with increased research, it has been discovered that H2S can act as an endogenous regulatory transmitter.
H2S is produced both endogenously within mammalian tissues and exogenously from several natural sources:
Because H2S is a gas under ordinary conditions, direct supplementation is impractical. Hydrogen sulfide is in a gaseous state under ordinary temperature and pressure, and in many cases is utilized in the form supplied from a pressure cylinder; medical applications have been limited since the pressure cylinder requires care in transportation and installation. As a result, several categories of H2S-releasing preparations have been developed:
Binz (1897) cited an earlier reference on the medicinal use of sulfur by the followers of Hippocrates. Sulfur-containing compounds thus have a documented presence in Western medical tradition stretching back to ancient Greece. In relatively recent historical times, elemental sulfur has been used as a laxative and as an ointment for treatment of scabies and fungal infections, uses that were considered effective. In addition, sulfur ointments were used for various other skin diseases, and colloidal sulfur was injected either intravenously or intramuscularly for treatment of tuberculosis, syphilis, and especially arthritis.
The injections, especially for arthritis, were probably an extension of the traditional treatment of rheumatism and various other conditions by baths in water from sulfur springs. The oral, purgative dose of noncolloidal sulfur was 2000–4000 mg. Sulfur in combination with molasses constituted a favorite "spring tonic" of earlier times. Its purgative action was due to hydrogen sulfide, which was formed by gradual reduction of a part of the sulfur.
Hot springs containing hydrogen sulfide are said to have efficacy in circulatory diseases and skin diseases, and the usefulness of hydrogen sulfide has been known since old times. Sulfur mineral springs are often highly valued for their healing qualities, most likely as a result of significant levels of H2S that are absorbed through the skin to help recharge cellular redox status. Scientific investigations of the effects of warm sulfur mineral springs are beginning to be published, demonstrating benefits in a number of pathologies including cardiovascular degeneration, skin ailments, wounds, breathing difficulties, rheumatoid arthritis, hepatic, gallbladder and kidney diseases, metabolic and urological disorders, insomnia, and neurological deterioration.
In Europe, where mineral water treatment is a part of traditional medicine, sulfur-based hot springs are used to treat conditions such as psoriasis, dermatitis, fungal infections, and even gynecological problems. Sulfur water and mud are also used to relieve joint conditions such as arthritis and rheumatism.
The long tradition of medicinal use of garlic — in ancient Egyptian, Greek, Roman, Chinese, Indian (Ayurvedic), and medieval European traditions — is relevant in the context of H2S biology. The consumption of garlic is inversely correlated with the progression of cardiovascular disease, although the responsible mechanisms remained unclear until modern research established H2S production as a key mediator. It has been proposed that H2S production from garlic-derived organic polysulfides provides the basis for the long-term beneficial effects obtained from the habitual consumption of garlic.
Three enzymes are recognized as endogenous sources of H2S in various cells and tissues: cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST).
Researchers identified that H2S is involved in a post-translational modification called S-sulfhydration of a large number of proteins. A variety of key proteins of different cellular pathways in mammals are sulfhydrated by H2S to regulate and affect the processes of cell survival/death, cell differentiation, cell proliferation/hypertrophy, cellular metabolism, mitochondrial bioenergetics/biogenesis, ER stress, vasorelaxation, inflammation, and oxidative stress.
At physiologically relevant concentrations, H2S relaxes vascular tissues, an effect mediated by the activation of ATP-sensitive K+ (KATP) channels in vascular smooth muscle cells (SMCs). H2S directly alters the activity of KATP channels without the involvement of second messengers.
H2S has emerged as a very potent antioxidant molecule via both direct and indirect actions. H2S directly interacts with reactive oxygen/nitrogen species and is involved in redox signaling.
H2S can donate electrons to the mitochondrial electron transport chain through sulfide:quinone oxidoreductase, consequently promoting oxidative phosphorylation and increasing mitochondrial ATP production. However, at higher concentrations, the toxicity of H2S is mainly due to the inhibition of cytochrome c oxidase (COX) in mitochondria, leading to chemical asphyxia of cells.
Leading the trend by nitric oxide and extending the approach by carbon monoxide, hydrogen sulfide (H2S) builds up momentum as the third gasotransmitter. Being produced by different cells and tissues in the body, H2S, alone or together with the other two gasotransmitters, regulates an array of physiological processes and plays important roles in the pathogenesis of various diseases from neurodegenerative diseases to diabetes or heart failure.
H2S is an endogenous neuromodulator and present studies show that physiological concentrations of H2S enhance NMDA receptor-mediated responses and aid in the induction of hippocampal long-term potentiation. Moreover, physiological concentrations of H2S in mitochondria have many favorable effects on cytoprotection.
Garlic oil polysulfides, diallyl trisulfide (DATS) and diallyl disulfide (DADS), react with GSH to produce H2S. DATS releases H2S immediately using GSH as a thiol-disulfide exchanger both in media and in cell culture, while DADS slowly releases H2S in the presence of GSH, making DADS potentially more preferable for achieving physiological effects.
H2S has been implicated in several physiological and pathophysiological processes such as long-term synaptic potentiation, vasorelaxation, pro- and anti-inflammatory conditions, cardiac inotropism regulation, cardioprotection, and several other physiological mechanisms.
In the vascular system, evidence is strong for a major role of H2S as a physiologic vasodilator. A progressive decline in endogenous H2S levels is associated with the onset of various cardiovascular age-related diseases.
SG1002 in Heart Failure — Phase I Clinical Trial: SG1002, a sodium polysulthionate, is a synthetic H2S prodrug that has completed a Phase I clinical trial for heart failure and has confirmed its safety and efficacy for restoring sulfate and nitric oxide levels in heart failure patients. Although SG1002 was shown to be safe, its long-term efficiency for cardiovascular diseases still needs to be confirmed.
Preclinical evidence: The protective effects of H2S on cardiac function in aging rats may be partly due to the inhibition of cardiomyocyte ferroptosis. Cardiac dysfunction associated with aging was closely related to decreased endogenous H2S levels and cardiomyocyte ferroptosis. H2S-regulated iron metabolism reduced oxidative stress levels in cardiomyocytes, inhibited cardiomyocyte ferroptosis, and protected cardiac function in aging rats. This evidence is preclinical and has not yet been replicated in human trials.
Garlic supplementation and H2S: A randomized, double-blind, placebo-controlled clinical trial found a negative correlation between organosulfur compounds of aged garlic extract (AGE) and obesity-induced inflammation. After taking AGE supplement at a dose of 3.6 g per day for six weeks, S-allylcysteine (SAC) reduced obesity-induced inflammation by releasing hydrogen sulfide (H2S) via increasing its endogenous products.
Evidence strength: Mechanistic and animal-model evidence is robust. A Phase I human trial with SG1002 confirms safety and biochemical restoration. Robust Phase II/III cardiovascular outcome trials are lacking as of the current literature.
The gaseous signaling molecule H2S critically modulates a plethora of physiological processes across evolutionary boundaries. These include responses to stress and other neuromodulatory effects that are typically dysregulated in aging, disease, and injury. H2S has a particularly prominent role in modulating neuronal health and survival under both normal and pathologic conditions.
Persulfidation and H2S signaling are compromised in several age-related neurodegenerative diseases, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and spinocerebellar ataxia (SCA).
A rationale exists for the use of H2S donor compounds in Alzheimer's disease, though finding the correct dosing strategy may be difficult. Abnormal H2S levels are implicated in central nervous system diseases such as Down syndrome and Alzheimer's disease.
As neuromodulation was the first functional role described for endogenous H2S in humans, it is unsurprising that H2S has been implicated as a key player in brain ageing.
Evidence strength: Human clinical evidence for neuroprotective use of H2S donors is scarce. While there is abundant evidence of the neuroprotective efficacy of H2S donors in rodents, Drosophila, and worm models, examples of translation to human disease are scarce. This remains a predominantly preclinical area.
Hydrogen sulfide (H2S), a common sulfur compound found abundantly in mineral-rich waters, has been notably recognized for its profound and significant anti-inflammatory effects. It is an endogenous mediator of inflammation and a potential cytoprotective compound.
Sulfur-containing compounds from garlic are considered to be potential anti-inflammatory mediators that reduce the clinical conditions related to chronic diseases. Recent studies suggest that the benefits associated with garlic-derived sulfur compounds are closely linked to H2S production.
Hybrid H2S-releasing NSAID (ATB-346): Some H2S-donating hybrid drugs have made it into clinical trials, including a Phase 2B study that demonstrated a reduction in gastrointestinal toxicity of the hybrid H2S-releasing analgesic/anti-inflammatory drug ATB-346, as compared to the NSAID naproxen that produces a similar inhibition of the inflammatory cyclooxygenase-2 (COX-2) molecule.
Evidence strength: The ATB-346 Phase 2B trial is the most advanced human trial for an H2S-based anti-inflammatory drug to date, but this is a pharmaceutical drug rather than a dietary supplement. The broader anti-inflammatory evidence base remains largely preclinical.
Hydrogen sulfide (H2S) modulates many biological processes, including ageing. H2S may be reduced in age-related diseases, and many preclinical studies suggest benefits of H2S donor molecules, especially for cardiovascular disease.
Hydrogen sulfide (H2S) has been recently recognized as a new player capable of influencing intracellular machinery involved in ageing and is viewed as a potential target for preventing cardiovascular diseases. Since many pathological conditions have been related to abnormally low levels of H2S in blood and/or tissues, and are amenable to treatment by H2S supplementation, development of safe and efficacious H2S donors has been undertaken with a sense of urgency; these prodrugs also hold the promise of becoming widely used for disease prevention and as antiaging agents.
Evidence strength: Preliminary and preclinical. Human intervention studies specifically for longevity endpoints are lacking.
Several lines of evidence suggest excessive gut microbial H2S production may be etiologically involved in a wide range of diseases, from colorectal cancer to ulcerative colitis. The relationship between H2S and the gut is biphasic: at low levels, hydrogen sulfide plays a role in gut health and cell signaling; but in excess, it becomes toxic to the gut lining, can damage epithelial cells, suppress beneficial hormones like GLP-1, and lead to systemic inflammation.
Evidence strength: The complex, dose-dependent role of H2S in the gut is established in preclinical and observational literature. Definitive human intervention trials for H2S modulation in GI disease remain limited.
Evidence is mixed on whether administration of hydrogen sulfide donors (such as NaHS) is able to improve glucose tolerance in diabetes. In mice fed normal chow, GYY4137 increased insulin resistance, while in an obesity model (mice fed a high-fat diet), GYY4137 increased insulin sensitivity. In the streptozotocin-induced diabetes model, elevated hydrogen sulfide was implicated in contributing to β-cell failure, and hydrogen sulfide administered at doses of 50–200 μM was found to decrease the viability of INS-1E cells in culture. In contrast, NaHS used at 100 μM was found to have a protective role in maintaining islet function and viability following high-fat feeding in rats. Differences in dose and duration of exposure may be a factor determining the overall effect of hydrogen sulfide on islet function.
Evidence strength: Mixed and inconsistent preclinical evidence. No robust human clinical trials on H2S donors for diabetes as of the current literature.
In vitro and in vivo studies have reported the anti-cancer potential of organosulfur compounds (OSCs), as they trigger biological effects leading to cell cycle arrest with accumulation of cells in G2/M, alteration of the microtubular network, modulation of Bcl-2 family protein expression patterns, and changes of the redox status. Despite these well-described effects, no OSC derivative is yet undergoing clinical trials even though their chemistry is well understood as OSCs act as hydrogen sulfide (H2S) donors.
The slow-releasing H2S donor GYY4137 caused concentration-dependent killing of seven different human cancer cell lines (HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11, and U2OS) but did not affect survival of normal human lung fibroblasts (IMR90, WI-38). Sodium hydrosulfide (NaHS) was less potent and not active in all cell lines.
Elevated endogenous H2S in colon cancer cells has been shown to regulate cell migration and invasion. Additionally, pharmacological inhibition of H2S production diminished the growth of cancer cells by suppressing basal respiration, ATP production, spare respiratory capacity, and glycolysis. This dual role highlights the complexity of H2S in oncology, where it may be tumor-promoting in some contexts and tumor-suppressing in others.
Evidence strength: Exclusively in vitro and animal model. No human clinical trials for H2S donors in cancer have been completed.
The therapeutic benefits of sulfur-rich mineral waters are increasingly recognized in both traditional and modern medical practices. These waters, often sourced from geothermal springs, contain various forms of sulfur, including hydrogen sulfide (H2S), thiosulfates, and sulfates. Sulfur compounds in mineral waters have demonstrated potent antimicrobial properties, effectively inhibiting the growth of pathogenic microorganisms such as Staphylococcus aureus, Candida albicans, and Cutibacterium acnes.
Sulfur-rich mineral waters have demonstrated therapeutic promise for various diseases, including arthritis, skin ailments, and heart diseases. H2S effects of thermal water treatments have long been studied for dermatological and clinical treatments.
Evidence strength: Balneotherapy with sulfur-rich waters has a long traditional use record and some clinical study support, particularly for dermatological conditions. However, study quality is heterogeneous and standardized protocols are lacking.
H2S-catalyzing enzymes such as cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase are differentially expressed in a variety of tissues and affect a variety of biological functions, such as transcriptional and posttranslational modification of genes, activation of signaling pathways in the cell, and metabolic processes in tissues.
The role of H2S in the nervous, cardiovascular, digestive, and respiratory systems has been examined, and the existence of endogenous H2S has been verified. H2S exerts a wide range of pathological and physiological functions in the human body, from the endocrine system and cellular longevity to hepatic protection and kidney function.
No universal established human supplementation dosage exists for H2S or H2S-releasing agents as dietary supplements. The following dosages are reported in specific studies and trials cited in the scientific literature:
There is no safety data in humans on the use of slow-release H2S donors as dietary supplements, and therapeutic windows for oral H2S-donating compounds in humans have not been formally established.
H2S has a narrow therapeutic window. Increasing the dosage of H2S leads to higher levels in blood plasma, but H2S concentrations in the µM range and above lead to neurological dysfunction and rapid cardio-circulatory failure leading to cardiac arrest, precluding the use of H2S in higher dosages.
H2S environmental concentrations of 100 ppm are immediately dangerous to life or health; concentrations greater than 500 ppm can cause a person to collapse within five minutes; and concentrations exceeding 700 ppm can cause immediate collapse and death within just one or two breaths.
Hydrogen sulfide is one of the leading causes of workplace gas inhalation deaths in the United States. According to the Bureau of Labor Statistics (BLS), hydrogen sulfide caused 46 worker deaths between 2011 and 2017.
The OSHA permissible exposure limit (PEL) for H2S is 20 ppm (29 CFR 1910.1000 Table Z-2) and is not to be exceeded at any time during an 8-hour shift, except if the exposure is 50 ppm for no more than 10 minutes in an 8-hour shift. The American Conference of Governmental Industrial Hygienists (ACGIH) recommends a threshold limit value (TLV) of 1 ppm as an 8-hour time-weighted average (TWA) and a short-term exposure limit (STEL) of 5 ppm.
Do not rely on the sense of smell to indicate the continuing presence of hydrogen sulfide or to warn of harmful levels. The "rotten egg" odor of hydrogen sulfide can be detected at low concentrations, but after a while, the ability to smell the gas is lost even though it is still present (olfactory fatigue). This loss of smell can happen very rapidly, and at high concentrations the ability to smell the gas can be lost instantly (olfactory paralysis).
High levels of H2S may be toxic to cells; however, the evidence does not suggest that slow-releasing H2S donor molecules would significantly increase plasma levels of H2S. High levels of H2S may be toxic to cells; however, the evidence does not suggest that slow-releasing H2S donor molecules would significantly increase plasma levels of H2S.
Other H2S donors, which release H2S gently, tend to produce secondary products or need to be given at high doses, leading to liver and kidney toxicity.
In a randomized controlled trial, after oral administration of 1 g or 3 g of dehydrated garlic powder, the organosulfur compound diallyl disulfide (DADS) and diallyl sulfide (DAS) were not detected in the urine samples after 6 and 24 hours. Allyl thiosulfates of garlic preparation undergo extensive metabolism, producing allyl methyl sulfide, essentially present in breath. This raises questions about the actual systemic delivery of H2S from dietary garlic supplementation at moderate doses.
Although numerous clinical studies have demonstrated the beneficial effects of garlic on cardiovascular disease progression, a sufficient number of studies show little or no beneficial effects. Critical reviews often cite differences in subject health status, trial duration, and unknown active constituents in various garlic preparations as nonuniform factors contributing to inconsistent outcomes.
The dual, context-dependent role of H2S in cancer — potentially tumor-promoting in cancer cells that co-opt endogenous H2S production for bioenergetics, and tumor-suppressing in others — means that H2S supplementation in oncological contexts requires caution and further study. The exact physiological and hazardous thresholds of hydrogen sulfide (H2S) in the human body are currently not well understood and need to be researched in depth.
Even the H2S from natural hot springs can be deadly. Several lives have been lost as a result of bathing in hot sulfurous spring waters in closed rooms.
The identification of H2S as a gasotransmitter has led to renewed interest during the last two decades, focusing on creating chemical tools for its physiological detection, determining its signaling functions in various organs and systems, and exploiting its biological signaling capacity for therapeutic benefits.
H2S is involved in many important cellular and physiological processes. Compounds that donate H2S to biological systems can be developed as therapeutics for different diseases. In comparison with synthetic chemical molecular compounds, natural products are considered safer and potentially more druggable.
Over the past 25 years, the H2S concept has gone from a toxic gas to a signaling molecule with potential clinical relevance. Despite this transition, various preclinical studies have shown that H2S affects physiological and pathological processes in the body; however, a detailed systematic summary of these roles in health and disease is lacking, and human clinical trials remain sparse across most indication areas.
Health conditions that Hydrogen sulfate may help support.
Body systems that Hydrogen sulfate may help support.
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