Abstract
“Poppers,” or inhaled alkyl nitrites, constitute a class of quasi-legal recreational drugs used to enhance sexual experience primarily through their vasodilatory effects. Thus far, the risks of alkyl nitrite inhalation remain poorly understood among the population of recreational users. Two concerns about potential neurotoxicity are often raised: first, comparison to other classes of inhaled organic solvents, and second, reference to a murine study by Cha et al. in 2016. These concerns do not appear to be well-founded. However, isopropyl nitrites specifically, rather than isobutyl or amyl nitrites, are known to cause adverse ophthalmic reactions and may pose a general neurotoxic risk. If isopropyl nitrites are avoided and recreational use is sufficiently limited, overall neurotoxic risk appears low.
Introduction
Inhalation of “poppers,” or alkyl nitrites, is commonly used in recreational settings to enhance sexual experiences. However, understanding of the risk profile of inhaled nitrites remains far from widespread, particularly concerns about potential neurotoxic risks.1 In the author’s experience, two claims are often colloquially advanced in support of this hypothesis; first, that general considerations about inhalation of “solvents” are applicable, in part or in full, to inhalation of alkyl nitrites, and second, that a study by Cha et al. in 2016 demonstrated neurotoxic effects of alkyl nitrites.2 We examine both claims in turn and find them to be largely unsupported. However, literature evidence supports the existence of neurotoxic effects of isopropyl nitrites specifically, and there is a risk of neurotoxicity as a secondary consequence of severe methemoglobinemia and consequent tissue hypoxia. These two risks are ameliorated by usage of non-isopropyl nitrites in the typical, sporadically inhaled manner, particularly if the user ceases inhalation upon self-observation of cyanosis.
Overview
When examining the mechanistic basis of toxicity resulting from inhalation of volatile organic solvents often abused by recreational users such as toluene, acetone, and ethylene glycol—hereafter referred to as “solvents”—we find that that alkyl nitrites are known to act through different mechanisms not expected to result in similar toxicities. The rapid metabolism of alkyl nitrites in plasma, in comparison to the slow poor absorption and metabolism of solvents, also limits exposure and consequent toxicity. Later, we review known acute and chronic symptoms of solvents, which include many co-occurring manifestations of neurotoxicity such as tremors, vision loss, and hearing loss, and contrast them with the symptomology of nitrite inhalation, in which the same symptoms are seldom reported.
With regard to the methodology of Cha et al. (2016), a number of limitations prevent generalization of their results to recreational human usage.2 For example, in their study, extremely high dosages of alkyl nitrites—less than an order of magnitude than the murine LD50—are injected intraperitoneally into mice, which differs drastically from typical recreational inhalation of very small doses at intervals separated by several minutes. Examination of the pharmacokinetic and toxicological parameters of inhaled alkyl nitrite suggests drastically different levels of maximal exposure in recreational users. Additionally, the murine assays used to support the claim of functional neurotoxicity, such as the Morris water maze or the rotarod test, cannot be interpreted alone as specific evidence of neurotoxic effects. They may be explained as simple fatigue or nontoxic modulation of neurological parameters, and their predictive value for human neurotoxicity of a given treatment is generally low.
Overall, concerns about the neurotoxicity of alkyl nitrites cannot be supported either by generalization from more well-known classes of organic solvents or by reference to the study of Cha et al. (2016). Furthermore, the known symptomatology of chronic recreational nitrite use is not indicative of neurotoxicity. Although it is conceivable that inhalation of alkyl nitrites might lead to neurotoxicity via currently unknown mechanisms or with a heretofore unrecognized clinical presentation, currently available evidence suggests the overall risk profile is low.
Two caveats to the above conclusion: First, retinal toxicity, a potential sign of neurotoxicity, has been observed in users of isopropyl nitrites, along with numerous colloquial reports of headache. Retinal toxicity is generally not observed with other alkyl nitrites. Second, excess inhalation of alkyl nitrites can lead to severe methemoglobinemia, which results in tissue and cerebral hypoxia. However, if recreational users self-limit inhalation of alkyl nitrites upon observation of cyanosis or pronounced fatigue, they are unlikely to experience methemoglobinemia to such an extreme degree.
Detailed comparison of solvent and alkyl nitrite neurotoxicity
Inhalation of volatile organic solvents found in commercial products such as paint thinner, lighter fluid, hair spray, permanent markers, etc. is a common form of recreational drug abuse, with lifetime prevalence in the United States of around 10%.3 They are understood to be highly neurotoxic via two general mechanisms. First, asphyxiation can result either from direct inhalation from a closed container such as a plastic bag or from irreversible displacement of oxygen from the lungs by inhalation of a vapor denser than air which is not readily absorbed.4–6 This has the potential to cause anoxic brain injury characterized by long-lasting cognitive and motor deficits.7 Second, solvents may exert direct neurotoxic effects via CNS exposure. Toluene, the most commonly abused solvent, exerts a wide range of effects on multiple neurotransmitter signaling pathways in the mesocorticolimbic system, which are generally thought to be responsible for its acute toxicity.8 Adhesives containing hexacarbons such as N-hexane or methyl butyl ketone damage the peripheral nervous system through disruption of neuronal axoplasmic flow, among other effects.9 Other solvents, such as trichloroethylene, benzene, dichloromethane, and so on, have also been associated with direct neurotoxicity.5 Generally, these effects are believed to be potentiated by the high lipophilicity and slow metabolism of these solvents, which allows them to preferentially diffuse into brain tissue with high exposure levels sustained over the course of an entire hour due to the slow rate of renal and hepatic conjugation reactions.10–12
Neither of these mechanisms clearly apply to the inhalation of alkyl nitrites, which are nearly immediately absorbed into the bloodstream before undergoing rapid hydrolytic decomposition with a half-life of under 2 minutes independent of concentration.13 Although alkyl nitrites have densities multiple times greater than that of air, there are no reported cases of asphyxiation due to displacement of oxygen, as expected of transient recreational exposure to small quantities which are readily absorbed, metabolized, and excreted. In principle, a recreational user could suffocate if they inhaled alkyl nitrites from a closed container with no inflow of oxygen, but that is not a common route of administration.14 A theoretical risk of cerebral hypoxia also exists due to declining oxygen availability associated with the progression of methemoglobinemia, but recreational use is self-limiting in this respect due to the onset of severe cyanosis, fatigue, and dyspepsia well before neurologically dangerous levels of methemoglobin are reached.15 Finally, no clear mechanistic basis has been identified for neurotoxicity of inhaled alkyl nitrites, which are used primarily for their vasodilatory effects; in contrast, inhaled solvents are known to produce hallucinatory and psychotic effects through a combination of neurotransmitter disruption and transient cerebral hypoxia.3
Even if a mechanistic basis for neurotoxic effects of alkyl nitrites is not presently known, that does not exclude the possibility that they are potent neurotoxins. However, comparison of the known symptomatology with well-established neurotoxins, such as inhaled solvents, is informative. If inhalation of a substance is a direct cause of neurodegeneration, then the presentation of dose-dependent acute and chronic neurovascular symptoms would be expected. For example, long-term inhalation of solvents is known to be associated with cognitive dysfunction, dementia, ataxia, insomnia, depression, optic neuropathy, sensorimotor dysfunction, and hearing loss.5,16–18 Although not all of the aforementioned symptoms may be observed in a given patient, chronic exposure to inhaled solvents typically presents with more than one of those symptoms, consistent with polyneuropathy.19 The severity of these symptoms have clearly reported dose-response relationships both in vivo and among recreational users.20,21 In contrast, recreational users of alkyl nitrites have reported only short-term effects (likely attributable in part to drug-induced methemoglobinemia) without any clear evidence of long-term psychological or neurological deficits.22 Furthermore, current medical advice on the management of inhaled nitrite usage does not list acute or chronic neuropathy as a relevant consideration.14 The one exception is retinal toxicity associated with use of isopropyl nitrites specifically, which raises concerns about general neurotoxic effects of isopropyl nitrite but has not been observed with usage of amyl or isobutyl nitrites.23,24 Overall, the known symptomatology of non-isopropyl alkyl nitrite inhalation does not support the hypothesis of either short- or long-term neurotoxic effects.
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