A practical, low-cost supplementation regime of vitamins C, B2, and E before recreational use of alkyl nitrates as partial prophylaxis against adverse effects

Abstract

“Poppers,” or inhaled alkyl nitrites, are commonly used recreationally to enhance sexual experience. Usage of inhaled nitrites is associated with both acute and chronic toxicity, but understanding of practical risk management strategies remains poor.1 Here, we examine one of the primary adverse effects of inhaled nitrites, methemoglobinemia. Drawing from an extensive assortment of published data, we propose that recreational users of poppers take oral antioxidant supplements (3 g vitamin C, 400 mg vitamin B2, and 800 mg vitamin E) two hours before anticipated usage. This supplementation regime has the potential to modestly ameliorate short-term methemoglobinemia associated with inhalation of alkyl nitrites.

Introduction

Methemoglobin (metHb) is formed by the oxidation of hemoglobin from the ferrous [Fe2+] to the ferric [Fe3+] state, which induces allosteric changes enhancing its affinity to oxygen and therefore impairing oxygen release to tissue.2 Typically, methemoglobin levels relative to the total pool of hemoglobin and methemoglobin (metHb%) are maintained at 1% or below through the action of cytochrome b5 reductase and nicotinamide adenine dinucleotide phosphate hydrogen methemoglobin (NADPH-MetHb) reductase.3 However, high methemoglobin concentrations result in  tissue hypoxia, leading to cyanosis, dyspepsia, and further complications.4

Alkyl nitrites are direct oxidizers of hemoglobin, and recreational inhalation of alkyl nitrites can lead to significant elevation of circulating metHb.3,5 This elevation is typically not associated with long-lasting sequelae, but has occasionally been observed to reach fatal levels.6 The consequent methemoglobinemia may also be exacerbated by hemolytic anemia caused by direct oxidative damage to the erythrocyte membrane.7,8 Transient cyanosis and fatigue resolving within 1-2 days, together highly suggestive of methemoglobinemia, are commonly observed from recreational inhalation of alkyl nitrites.9–12 Practical strategies to reduce the severity of alkyl nitrite-induced oxidative stress and methemoglobin formation are therefore of great interest.

Clinical presentation of methemoglobinemia is typically treated with one or more intravenous injections of 1-2 mg/kg methylene blue, which is metabolized to leukomethylene blue and directly reduces methemoglobin to hemoglobin.3 However, intravenous injection of methylene blue is not practical in a recreational setting. Additionally, oral methylene blue is associated with plasma concentrations and an area under the curve approximately 10-fold lower than with i.v. treatment.13 A separate study observed that oral intake of 500 mg of methylene blue provoked immediate nausea in over half of the study participants due to its bitter and metallic taste.13 It is therefore unlikely that oral methylene blue, unless formulated and dosed appropriately, can be used as either a prophylactic or treatment for methemoglobinemia induced by recreational nitrite inhalation. Finally, exposure to methylene blue may result in CNS toxicity, suggesting that treatment should be reserved for serious cases of methemoglobinemia.14

Beyond methylene blue, alternative treatments for methemoglobinemia have been proposed with varying degrees of evidence. The most prominent alternative, intravenous vitamin C (ascorbic acid), has been successfully used to treat cases of methemoglobinemia where methylene blue was unavailable or contraindicted.15–18 Additionally, in a patient with congenital methemoglobinemia, daily oral administration of vitamin B2 (riboflavin) (60 mg/day) and vitamin C (600 mg/day) successfully reduced metHb% from 18.2% to 6.4% after 1 week.19 Finally, studies in rats suggest that addition of vitamins C or E (α-tocopherol) to food partially protects against nitrite-induced methemoglobinemia.20–22 Beyond these studies, a number of in vitro experiments suggest that other antioxidants such as carnosine and N-acetylcysteine may accelerate the reduction of methemoglobin, but it is unclear to what extent these results are applicable in man.23 In fact, a randomized controlled trial in healthy volunteers identified a statistically significant elevation of metHb% as a result of intravenous N-acetylcysteine treatment.24

Hundreds of different antioxidants have been described in the literature.25 However, due to the limited and uncertain evidence regarding their applicability to methemoglobinemia, we restrict our attention to the three antioxidants with evidence for their efficacy in vivo: vitamins C, B2, and E. All three of these are available as low-cost, over-the-counter products, as well as well-characterized safety profiles and pharmacokinetics of oral dosing.

We first examine the metabolism of inhaled alkyl nitrites and the resulting dynamics of methemoglobin formation and reduction in the absence of pharmacological treatment to establish the expected time course of methemoglobinemia as a result of recreational nitrite usage. Next, we review each of vitamins C, B2, and E in detail. For each antioxidant, we first use data from in vitro studies of methemoglobin reduction to establish desired levels of plasma exposure, then review the pharmacokinetics of oral supplementation to determine a suitable dosing regimen. Taking into consideration the quality and quantity of evidence supporting each antioxidant, we propose 3 g vitamin C, 400 mg vitamin B2, and 800 mg vitamin E, dosed orally 2 hours before recreational usage of inhaled alkyl nitrites, as a potentially effective form of prophylaxis against methemoglobin accumulation and hemolytic anemia.

Dynamics of methemoglobin formation and reduction after alkyl nitrite inhalation

Inhaled nitrites almost immediately enter circulation and undergo rapid metabolism with plasma half-lives of 1-2 minutes, consistent of recreational reports that the “high” of inhalation only lasts for several minutes.1,26,27 A study of methemoglobin formation in healthy adult volunteers found that methemoglobin levels increased gradually and dose-dependently over 3 hours of nitric oxide inhalation.28 At the highest concentration of nitric oxide tested, 512 vpm, treatment was discontinued upon attaining 5% metHb, after which methemoglobin concentrations decayed at a rate of approximately 2% per hour. Furthermore, studies of intravenous or oral sodium nitrite administration in rats suggest roughly similar kinetics for the reduction of methemoglobin to hemoglobin, subject to the caveat that the levels of nitrite exposure are extremely high and remain in the circulation for over an hour post-dosing.29 Taken together, these studies suggest that inhalation of alkyl nitrites cause rapid spikes in metHb% which slowly decay over the course of several hours.

Bluish or purplish discoloration of the skin, known as cyanosis, begins to present at 10-20% metHb.2 Concentrations of 20-30% are associated with lightheadedness and fatigue, and concentrations above 50% are associated with coma, seizures, and death.2 Recreational inhalation of alkyl nitrites is likely self-limited by the onset of serious fatigue and the visual observation of cyanosis, so typical metHb levels in recreational use are unlikely to exceed 20-30%. Because high metHb% is typically treated with reducing agents such as methylene blue, the natural time course of metHb reduction from levels as high as 20-30% down to asymptomatic levels of 1-2% is not well documented. However, the primary mechanism of methemoglobin reduction is via the action of constitutively expressed enzymes that counteract naturally occurring oxidation of hemoglobin.30,31 It is unclear to what extent higher methemoglobin levels induce higher expression of reducing enzymes; therefore, a conservative estimate of reduction kinetics can be obtained from extrapolating the previously observed rate of 2% metHb reduction per hour starting from an initial level of 5% metHb.28 A light user of inhaled nitrites, reaching at most 5% metHb, would expect to return to baseline methemoglobin levels within 2 hours; a moderate user, observing cyanosis and light fatigue associated with 10% metHb, would need 4 hours; finally, a very heavy user who attains maximal levels of 30% metHb might need as long as 14 hours. This model is corroborated by a rare study of healthy volunteers inhaling for 12 minutes continuously from a bottle of recreationally used, chromatographically pure isobutyl nitrite, in which the maximum metHb concentration observed was approximately 8%, with a linearly declining concentration curve after discontinuation reaching undetectable levels at 3 hours post-treatment.32 Typical recreational use, which is sporadic rather than continuous, is unlikely to exceed 12 total minutes of inhalation in a single session, so recommendations for prophylactic treatment assuming 10% maximum metHb and decay to physiological baseline within 4 hours post-usage are likely relevant to the vast majority of recreational users.

Fatigue lasting throughout the day after usage has been reported among recreational users of inhaled nitrites.11,33 Notably, observation of cyanosis does not seem to frequently co-occur in the same reports, suggesting that this long-lasting fatigue is not due to persistence of methemoglobin but instead to other effects of inhaled nitrites such as hemolytic anemia, immunosuppressive effects, or nonspecific inflammation and cytotoxicity.8,34 Given considerable variability between different brands of recreational alkyl nitrites, or even between different batches of the same product, it is also plausible that uncharacterized impurities or additives also play a role in generating these symptoms.35

Pharmacodynamics and pharmacokinetics of oral vitamin C supplementation

Vitamin C has been successfully used as an intravenous treatment for acute methemoglobinemia at doses ranging from 1 to 10 g.16,18 A 3-compartment pharmacokinetic model suggests that these i.v. doses are associated with maximal plasma concentrations ranging from 1 to 5 mM.36 Vitamin C has a plasma protein binding of roughly 24%, suggesting maximal unbound exposures of  0.75 to 4 mM. These treatment regimens are consistent with a prior in vitro study of human erythrocytes which found post-nitric oxide treatment with 1 mM and 10 mM vitamin C, but not 0.1 mM, to significantly accelerate methemoglobin reduction.37

Extremely high levels of vitamin C exposure are themselves associated with a theoretical risk of methemoglobinemia. In an in vitro study of human erythrocytes, 10 mM vitamin C significantly increased metHb% levels.38 Moreover, i.v. treatment with 30 g vitamin C (predicted maximum plasma concentration of approximately 10 mM with exposure to >5 mM for 3 hours post-infusion) induced acute methemoglobinemia and hemolytic anemia in a woman with glucose-6-phosphate dehydrogenase deficiency.36,39 However, this concern does not apply to oral dosing of vitamin C, in which bioavailability declines dramatically with the size of the dose.40 Single oral doses of 1.25 g vitamin C have been shown to produce maximal plasma concentrations of below 200 μM at approximately 2-3 hours after dosing with a subsequent half-life of 1-2 hours, and pharmacodynamic modeling suggests that a single oral dose of 3 g would result in prolonged sustainment of around 200 μM in circulation attained 2.5 hours after dosing and maintained for approximately 3 hours afterward.36,40 Note that although an oral dose of 3 g is well in excess of the recommended daily consumption limit of 2 g, vitamin C is generally well tolerated and excess short-term supplementation is unlikely to result in serious adverse effects.41

One legitimate question is whether or not exposure to plasma concentrations of vitamin C at or below 200 μM is likely to have any effect on nitrate-induced methemoglobinemia, considering that most treatment regimens effectively introduce circulating levels of vitamin C an order of magnitude greater. Although addition of 100 μM ascorbic acid was not found to significantly affect methemoglobin reduction in an in vitro study, it is difficult to directly generalize to the case of human oral supplementation.37 One positive indication comes from a case study of a patient with type I congenital methemoglobinemia where daily oral administration of 600 mg vitamin C and 60 mg vitamin B2 reduced metHb from 18.2% to 6.4% over the course of one week.19

In summary, these data suggest that supplementation of 3 g vitamin C approximately 2 hours before light recreational use of alkyl nitrites (where cyanosis is not observed) will result in exposure to high plasma concentrations of vitamin C throughout the expected duration of methemoglobin levels. This supplementation, if infrequent, is unlikely to itself result in significant adverse effects. If cyanosis or other symptoms of serious methemoglobinemia are observed, additional maintenance doses of 1-2 g may be advisable at 4-hour intervals, albeit at the risk of temporary gastrointestinal upset.

Pharmacodynamics and pharmacokinetics of oral vitamin B2 supplementation

Much less information is available regarding the ability of vitamin B2 (riboflavin), either i.v. or oral, to treat methemoglobinemia. Although many articles describe vitamin B2 as one of multiple treatment options, the author was only able to locate a single case study, where 600 mg oral vitamin C was combined with 60 mg oral vitamin B2.19 A pharmacokinetic study in human volunteers found that oral administration 20, 40, or 60 mg of vitamin B2 were associated with very similar plasma concentration curves, with maximal plasma concentration attained at 1-5.2 hours after dosing then declining to half-maximal approximately 2 hours later.42 Although the 60 mg dose resulted in a higher average maximal plasma concentration of vitamin B2 compared to the 20 and 40 mg doses (300 nM vs. 200-220 nM), the difference was not statistically significant; however, that is partially attributable to the small sample sizes used in the study.42 Several clinical studies report efficacious treatment of various indications with daily oral doses of 400 mg vitamin B2, but pharmacokinetic data are not available for these studies so it is unclear what level of plasma exposure was achieved.43–45 Nevertheless, doses of 400 mg were extremely well tolerated with very minor incidence of nonserious adverse events.45

With such limited data, it is difficult to draw firm conclusions, but a tentative recommendation can be made. Oral supplementation of 400 mg of vitamin B2 approximately 2 hours before recreational nitrite inhalation (without the appearance of cyanosis) will result in high plasma concentrations of vitamin B2 throughout the duration of elevated methemoglobin without significant risk of gastrointestinal upset or other adverse effects. Conveniently, over-the-counter formulations of vitamin B2 supplements are often available in dosages of 400 mg per capsule. Additional maintenance doses may be advisable in cases of more serious methemoglobinemia.

Pharmacodynamics and pharmacokinetics of oral vitamin E supplementation

Although vitamin E refers collectively to a number of different tocopherols and tocotrienols, α-tocopherol is typically the primary form under consideration in studies of antioxidant ability, although physiological interconversion between tocopherols and tocotrienols has been described.46 Compared to vitamins C and B2, even less information exists regarding the potential of vitamin E as a treatment of methemoglobinemia. The author was unable to identify any directly relevant studies in man, although there are several reported experiments in Sprague-Dawley rats.20–22 Additionally, an in vitro study found a dose-dependent relationship between addition of 5, 10, or 20 mM vitamin E and the rate of methemoglobin reduction.38 A separate study in vitro found that co-administration of vitamins C and E protected against peroxidation of the lipid bilayer, suggesting that supplementation of vitamins C and E may also protect against hemolytic anemia induced by inhaled nitrates.47

Absorption of orally dosed vitamin E is relatively poor, with maximal plasma concentration reached 3-6 hours after dosing depending on the particular tocopherol or tocotrienol. A number of clinical studies have used oral dosages of up to 800 mg per day (some with α-tocopherol alone and some with a mix of different tocopherols and tocotrienols) without the identification of serious adverse events.48 Most studies did not report circulating levels of vitamin E, so the relationship between plasma exposure and reported effects is unclear.48

With such scant evidence, no firm recommendation can be made, but practical considerations suggest matching the supplementation of vitamin E to be simultaneous with vitamins C and B2, despite suboptimal absorption kinetics. It is unclear if a high dose is significantly more effective than a low dose. It is also unclear which tocopherol or tocotrienol would be most effective in the context of methemoglobinemia and hemolytic anemia. However, since oral supplementation is well tolerated, a high dosage (up to 800-1,000 mg) of a mixture of different tocopherols and tocotrienols may be tentatively recommended.

Conclusion

Recreational inhalation of alkyl nitrites is associated with a number of adverse effects, including methemoglobinemia, the elevation of circulating methemoglobin levels during and after inhalation of nitrites. Methemoglobinemia, characterized by cyanosis, fatigue, and dyspepsia at low severities, significantly reduces quality of life and is a risk factor for development of further complications; therefore, practical prophylactic measures for recreational users of inhaled nitrates would be of significant value.

We examined the time course of methemoglobinemia resulting from inhaled nitrites and determined that methemoglobin concentrations are expected to return to baseline levels 2-4 hours after light usage of inhaled nitrates (with at most minor cyanosis) and up to 14 hours after heavy usage (extreme weakness and fatigue). Next, we reviewed the literature supporting usage of vitamins C, B2, and E as treatments for methemoglobinemia, and proposed a supplementation regime of 3 g vitamin C, 400 mg vitamin B2, and 800 mg vitamin E taken orally 2 hours prior to light-to-moderate recreational inhalation of alkyl nitrites. This supplementation regime exposes the subject to high circulating concentrations of vitamins C, B2, and E at the same time that they are expected to experience high circulating levels of methemoglobin, and therefore may reduce the severity and shorten the time-to-recovery of alkyl nitrite-induced methemoglobinemia by directly reducing methemoglobin into hemoglobin. This supplementation regime may also protect against hemolytic anemia or other forms of acute, nitrite-induced oxidative stress.

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October 19th, 2022 | Posted in Biology

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