Assessing Popper Purity—Implications for the Regulation and Recreational Use of Alkyl Nitrites

Abstract

Alkyl nitrites (“poppers”) are a diverse class of volatile chemical compounds with a varied legal and medical history. Though once commonly prescribed to treat angina, popper use is now almost exclusively recreational. Currently, poppers are widely available and sold legally under labels like “solvent cleaner”, despite marketing suggesting they are meant to be consumed. As a result, there is little incentive for producers to implement robust quality controls to protect users. In this study, nine common popper brands were analyzed using hydrogen-1 and carbon-13 nuclear magnetic resonance spectroscopy to assess the presence of impurities. Physical labels on all nine samples indicated the contents were “pure” isobutyl nitrite, despite contradictory online marketing in several cases. Spectral results showed isobutyl nitrite was present in all popper samples. However, there was evidence that various unlabeled compounds were also present in all samples. The identity and concentration of these contaminants were not clear, but the seemingly ubiquitous presence of impurities and lack of consistency in the tested samples are concerning and may represent a threat to users’ health. We hope the results of this study draw attention to the potential dangers of recreational popper use and the need to reassess how these compounds are regulated.

1. Introduction

Alkyl nitrites are a group of volatile organic compounds that are alkyl esters of nitrous acid and alcohols, and they are commonly used as recreational psychoactive substances. Amyl nitrite, a member of this group, has been used medically since 1867, when its rapid vasodilatory effects were identified as a remedy for angina pectoris [1,2]. Amyl nitrite is still listed as a prescription medication for the treatment of angina and has been recommended as a treatment for acute cyanide poisoning [3]. However, it is rarely used in practice due to its side effect profile and the development of more efficacious vasodilators [1]. Instead, the popularity of alkyl nitrites now comes almost exclusively from their use as recreational drugs [4,5,6]. When alkyl nitrites are used recreationally, they are often referred to by the name “poppers”, a term derived from when prescription amyl nitrite was administered by crushing or popping small ampules containing the volatile liquid and inhaling the vapors [7]. Today, “poppers” is a general descriptor for any alkyl nitrite inhalant intended for recreational use.

Though the original popper, amyl nitrite, was deemed safe enough to be deregulated and was available over-the-counter as recently as 1969, increasing recreational usage prompted tighter legal controls to limit its availability [4]. As a result, recreational popper use has shifted toward other chemical species in the alkyl nitrite family [4,8,9]. In recent decades, there have been several bans on specific alkyl nitrite compounds in the US and elsewhere; however, popper manufacturers have routinely circumvented legal regulation by altering the chemical structure of the alkyl nitrite species they produce [5,10,11,12]. Similarly, poppers are now labeled and sold as products not meant for human consumption, further minimizing legal oversight [13]. Today, the most widely available alkyl nitrite compounds are isobutyl or isopropyl nitrite, neither of which have an established safety profile [11].

The psychoactive effects of alkyl nitrites are mediated by the release of nitric oxide, a potent vasodilator that increases cerebral blood flow and induces striatal dopamine release [12,14]. Inhalation of alkyl nitrites results in rapid euphoria, smooth muscle relaxation, and sexual arousal, making them popular in nightclubs and during sex [4,6,15]. Poppers are most often associated with men who have sex with men (MSM), partially due to their ability to facilitate anal intercourse; however, popper use is common in many demographics, particularly among other sexual minorities, clubgoers, and younger individuals [5,10,15,16]. In countries like the United States or the United Kingdom, where alkyl nitrites are not regulated as a class, they remain one of the most commonly used recreational substances, with estimates suggesting that 3.3% of all adults and 35.1% of gay men have used poppers in their lifetime [5,6].

The prevalence of popper use can be partially attributed to their widespread availability and perceived safety profile [12,17,18]. Though inhalation of pure amyl nitrite in a controlled environment is highly unlikely to cause harm in most people, recreational popper use comes with many risks that are not immediately evident [19,20]. Besides the obvious risks of hypotension, syncope, intoxication, and overdose, adverse events associated with popper abuse also include vision disturbance, maculopathy, chemical burns, and methemoglobinemia [20,21,22,23,24,25,26,27]. It is not clear whether these outcomes are primarily due to adulterants present in poppers, specific alkyl nitrite compounds, or are indiscriminate consequences of any alkyl nitrite misuse.

Contamination or ingestion of impurities are risks that inherently apply to the recreational use of any unregulated substance [28]. However, with poppers, this issue may be concealed by the pseudo-legal status of this drug class. While regulation has limited the availability of some older alkyl nitrite species, novel compounds, like isobutyl nitrite, remain legal and are widely sold as solvents, cleaners, or room odorizers [7,8,28,29]. This labeling scheme may help producers avoid oversight from the Food and Drug Administration, and despite public FDA consumer updates regarding risks and threats, their packaging and status in popular culture make it clear they are meant to be inhaled [8,29]. Further, the legacy of the amyl nitrite as a high-purity prescription drug with a relatively favorable safety profile may now be inappropriately assumed for all poppers [19,20].

Currently, there are a few published studies evaluating the composition and purity of popper products available for sale. Frequently, poppers are labeled as “pure” alkyl nitrite compounds, but case reports suggest that poppers may contain mixtures of different alkyl nitrite species or contamination with harmful solvents, though this has not yet been widely assessed [8,14]. Given the prevalence of recreational popper use, limited regulatory oversight, and lack of incentives for manufacturers to implement meaningful quality controls or describe safe dosing and usage, the potential for harm to users is concerning. And unlike other recreation drugs where the same risks of mislabeling, contamination, and overdose are generally well understood, popper users may be entirely unaware [14].

In this exploratory study, we evaluate the chemical composition of nine popular popper brands using hydrogen and carbon nuclear magnetic resonance (NMR) spectroscopy to better understand the quality of these common recreational drugs. The primary aim of this study is to assess the purity of common popper brands currently on the market in order to test our hypothesis that recreational poppers contain chemicals not listed on their labels.

In our analysis, we found evidence supporting our hypothesis. Despite inconsistencies in the marketing of several brands, labels on all popper samples included in this study indicated that their contents were “pure” isobutyl nitrite. By comparing sample NMR spectra to a pure isobutyl nitrite control, our analysis indicated that isobutyl nitrite was present in all samples. However, we found evidence suggesting a variety of unidentified contaminants or impurities were also present in all poppers tested. Though far from an exhaustive analysis, these results indicate that contaminants may be a common feature in recreational popper supplies. Both users and clinicians should be aware that recreational popper ingestion carries the risk of exposure to chemicals beyond the specific alkyl nitrite listed on the label.

2. Materials and Methods

2.1. Sample Acquisition

Nine different popper samples were legally purchased from a popular online distributor based in the United States. Though one distributor was used for sample purchasing, the specific brands being sold were available on other similar sites and in brick-and-mortar gas stations, sex shops, and smoke shops. At the time of purchase, a total of 24 different popper products were listed for sale, with online descriptions suggesting at least 4 unique alkyl nitrite species were available. The 9 study samples were chosen based on the popularity rating listed by the distributor (highest score, 5-star scale).

2.2. Nuclear Magnetic Resonance Spectroscopy

Nuclear magnetic resonance (NMR) is a powerful analytic tool for analyzing the molecular structures of organic chemicals. NMR based on common nuclei, like hydrogen-1 (H1) and carbon-13 (C13), is widely used in chemical analysis and can provide information about chemical structures, conformation, bond connectivities, and intermolecular interactions [30]. In H1 NMR spectroscopy, the location of chemical shifts (spectral peaks), measured in parts per million (ppm) units, is affected by the nearness of molecular hydrogen atoms to functional groups, such as electronegative atoms and unsaturated hydrocarbon bonds. The structure of those peaks (splitting pattern) changes according to the numbers of protons on neighboring carbon bonds. By comparison, C13 NMR spectroscopy provides direct information about the carbon atoms and chemical identity of a molecular structure based on their proximity to electronegative functional groups in a molecule. Though spectral results are frequently complex and may be difficult to completely assign, H1 NMR spectroscopy and C13 NMR spectroscopy are widely accepted tools for chemical structure analysis and, compared to liquid chromatography–tandem mass spectrometry or gas chromatography–mass spectrometry, provide more comprehensive information about the molecular structure of components, do not require a reference standard for quantification, and do not require separation prior to analysis [30].

2.3. Sample Preparation and Spectral Analysis

Despite online descriptions advertising numerous alkyl nitrite species, labeling on the physical packaging of all samples indicated that the contents were pure isobutyl nitrite (synonym: 2-methylpropyl nitrite; linear formula: (CH₃)₂CHCH₂ONO). Deuterated chloroform (CDCl3) (Sigma Aldrich, St. Louis, MO, USA) was used as the solvent for NMR, as alkyl nitrites are minimally soluble in water. Samples were diluted in a 1:4 volumetric ratio using glassware. Several samples formed a white precipitate during dilution. In these instances, the precipitate was filtered out before loading the samples into NMR cuvettes.

One half milliliter of each sample mixture was loaded into separate 5 mm cuvettes and wrapped in foil to prevent photochemical degradation. Each sample was run for carbon-13 (C13) and hydrogen-1 (H1) detection using the A2 Avance III 500MHz NMR instrument (Bruker Corporation, Billerica, MA, USA). Spectra were normalized to correct for sample oversaturation. Spectral results were analyzed using the MNova software (Mestrelab, Santiago, Spain (version 11.0.3)). Spectra from all nine samples were stacked and relevant chemical shifts were plotted (Figure 1, Figure 2 and Figure 3). Absolute peak intensities (peak heights) were omitted from the final plots to allow for spectral stacking. Relative peak heights can be used to quantify the relative abundance of different functional groups in each sample. In both the C13 and H1 NMR, tetramethylsilane (TMS) was used to define the 0 ppm point.

For both H1 and C13 NMR, control spectra for pure isobutyl nitrite were needed as a comparison group. An external control was the only source of high-fidelity isobutyl nitrite available. Spectra produced by Sigma-Aldrich using the same experimental protocol described above were accessed through SpectraBase (Wiley Science Solutions, Hoboken, NJ, USA) and included as a comparison [31].

Due to the complexity of interpreting proton and carbon NMR, determining the identity of most contaminants was outside the scope of this investigation. Instead, the analyses were focused on identifying the presence or absence of the alkyl nitrite species listed on the packaging and whether obvious contaminants were present.

3. Results

3.1. Popper Marketing and Labeling

Nine different popper products were purchased and analyzed in this study.

Table 1. Sample identities and product descriptions.

Sample Number	Brand Name	Advertised Use	Chemical Identity (Listed Online)	Chemical Identity (Physical Bottle)
1	Rush	Solvent cleaner	Isobutyl nitrite	Isobutyl nitrite
2	Real Gold Poppers	Liquid aroma	Isobutyl nitrite	Isobutyl nitrite
3	PWD Super Rush	Solvent cleaner	Isobutyl nitrite	Isobutyl nitrite
4	Brown Bottle	Clock cleaner	Isobutyl nitrite	Isobutyl nitrite
5	Ecstasy	Clock cleaner	Not listed	Isobutyl nitrite
6	Flexx Extreme Strong	Solvent cleaner	Alkyl nitrite	Isobutyl nitrite
7	Jungle Juice Plus	Clock cleaner	Amyl nitrite	Isobutyl nitrite
8	Brazil	Solvent cleaner	Cycloamyl nitrite	Isobutyl nitrite
9	Rochefort	Leather cleaner	Not listed	Isobutyl nitrite

summarizes the information provided for each sample (both as advertised online and as described on the physical packaging of the samples). Regarding their online descriptions, the amount of information available for each product varied. Across the nine samples, online listings described four as isobutyl nitrite, one as amyl nitrite, one as cycloamyl nitrite, and one as “alkyl nitrite”. There was no specific alkyl nitrite compound listed for two samples.

The descriptions on the physical packaging of the samples did not reflect the diversity advertised online. Labels of all nine samples listed “pure” isobutyl nitrite as the sole chemical compound. The uses listed for the samples were clock cleaner, liquid aroma, solvent cleaner, and leather cleaner. Despite these industrial descriptors, most product advertisements and packaging included overt references to their use as an inhalant. This included advertising the smell of the products, their physiologic effects, duration, and strength. None of the labels described dosing.

Table 1 Legend

Table 1 provides a summary of the descriptions, advertising, and physical labeling of each popper sample analyzed in this study. This includes the brand name, product description (advertised use), specific alkyl nitrite chemical species advertised online, and the chemical contents listed on the physical packaging. Sample numbers correspond to the sample identities of the stacked spectra in Figure 1, Figure 2 and Figure 3.

3.2. H1 Spectra

Though all samples contained the peaks and splitting patterns characteristic of the functional groups in isobutyl nitrite, various additional peaks were also clearly present in all nine samples. Differences in the spectra of each popper sample indicate differences in the chemical structure of the principal molecules or the presence of other chemical species. The clearest difference between the pure isobutyl nitrite control and the samples was located between 1.4 and 3.3 ppm (Figure 1). This area of the H1 spectra also contained the highest level of variability between samples, illustrating the lack of consistency across these products despite all labels indicating that they were pure isobutyl nitrite. The multiplet located at 2 ppm corresponds to the single hydrogen on the second carbon of isobutyl nitrite, split by the two neighboring methyl groups and the alkane hydrogen pair attached to the carbon–nitrite functional group. This same peak and coupling pattern is present in all samples, indicating that isobutyl nitrite is likely present in all samples. The complete H1 spectrum of the samples also supports this conclusion, as all nine samples contain the three peaks characteristic of isobutyl nitrite (at approximately 1, 2, and 4.5 ppm).

Notably, all sample spectra also contain a multitude of additional, heterogeneous peaks, suggesting varying chemical contaminants are also present in each sample (seen both within the ppm range of Figure 1 and across the rest of the H1 spectrum). Some contaminants are identifiable. For instance, the multiplet at 1.8 ppm is presumably from isobutanol, the primary decomposition of isobutyl nitrite, and is present in all samples (structural analog to the multiplet peak of the proton at 2 ppm in isobutyl nitrite). The remaining peaks are unexplained and likely correspond to varying chemical contaminants present in the different samples.

Figure 1 Legend

Figure 1 shows the stacked proton (H1) nuclear magnetic resonance (NMR) spectra in the 1.4–3.3 parts per million (ppm) range. The x-axis corresponds to the chemical shift position (in ppm units), and the y-axis indicates the sample number. The experimental samples are located above the x-axis (labeled 1–9 according to Table 1 sample assignments), and the control is at the bottom. Absolute peak intensities (peak heights) were omitted for spectral stacking. Relative peak intensities are unchanged and represent the number of hydrogens present in each chemical shift.

3.3. C13 Spectra

Similar to the H1 spectra, C13 NMR of the nine samples showed that functional groups consistent with isobutyl nitrite’s chemical structure were present in all samples (Figure 2). Most notably, a peak near 75 ppm, presumably corresponding to the nitrite group (nitrosooxy functional group; R-ONO), is seen in the control and all samples. The triplet peak at 77 ppm is due to the carbon in the solvent (CDCl3). The number of unique carbons present in isobutyl nitrite implies there should be a total of three peaks in the spectra. The control follows this pattern with peaks at 75, 28, and 19 ppm; however, the spectra of the nine samples contain many additional peaks, indicating the presence of electromagnetically unique carbon atoms and what appear to be a range of unidentified functional groups not present in isobutyl nitrite. Some of these peaks are congruent with the decomposition product, isobutanol, but additional, heterogeneous peaks are also present. The clearest example of this variability is seen in the 150–180 ppm range (Figure 3). Here, there is a peak at 173 ppm present in seven of the nine samples, likely indicating the presence of a carboxyl or carboxylic acid ester group in these samples, which are not found in alkyl nitrites.

3.3.1. Figure 2 Legend

Figure 2 shows the stacked carbon-13 (C13) NMR spectra of the experimental samples and the control in the 51–78 ppm range. All samples have a peak at 75 ppm, characteristic of the carbon–oxygen bond of the nitrosoxy group present in alkyl nitrites. The triplet present in all samples at 77.5 ppm corresponds to the deuterated chloroform (CDCl3) solvent. Absolute peak intensities are omitted. Relative peak intensities are unchanged and represent the number of carbons present in each chemical shift.

3.3.2. Figure 3 Legend

Figure 3 presents the stacked C13 NMR spectra of the experimental samples and the control in the 163–181 ppm range. The doublet peak present in samples 2 and 4–9 at 173 ppm is most consistent with carboxyl or carboxylic acid ester functional groups, neither of which is present in isobutyl nitrite. Absolute peak intensities are omitted. Relative peak intensities were not adjusted.

4. Discussion

The focus of this investigation was to determine whether impurities are present in commonly sold popper products, given that there is little regulatory incentive for manufacturers to implement stringent quality controls. In this study, we assessed the chemical composition of nine popper brands and compared them to an isobutyl nitrite control spectrum using H1 and C13 NMR spectroscopy. Though the marketing for these popper brands advertised a range of different alkyl nitrite species, their physical packaging claimed they were all “pure” isobutyl nitrite. H1 and C13 NMR analyses indicated that isobutyl nitrite was present in all samples. Clear discrepancies between sample and control spectra were present in every popper brand tested, suggesting contaminants or impurities were also present in all samples, despite their purported purity. Other than isobutanol (isobutyl alcohol), the decomposition product of isobutyl nitrite, the identity of these contaminants is unknown, as is their potential for harm. But their presence suggests that recreational users may face additional exposure risk when taking poppers.

The health implications of these findings are concerning. Despite the common belief that alkyl nitrites are relatively harmless, there is ample evidence in the literature that popper misuse has the potential to cause a range of physical harms. Commonly, recreational popper use can cause hypotension, headaches, and intoxication [4,9]. More severe injuries associated with popper use include vision disturbance, maculopathy, and dermatitis or chemical burns [8,20,22,23,24,25]. Cases of nearly fatal outcomes have also been reported as a result of popper-induced methemoglobinemia, hypoxemia, hemolytic anemia, and overdose [17,21,26,27,32,33]. Though serious adverse events appear to be rare, the popularity and accessibility of poppers as a recreational substance may mean the cumulative effect on public health is meaningful [11,14].

This risk of injury is likely exacerbated by the apparent inconsistencies among available popper brands. Published reports on the adverse effects of popper use suggest that different popper brands have varying risk profiles. For instance, a case series studying popper-induced complications noted that among habitual users, adverse events often occurred soon after users switched popper brands [8]. Similarly, animal studies suggest that individual alkyl nitrite species have different abuse potentials and differential impacts on memory and cognitive function [12,34]. Though we are unable to quantify the health-related risks associated with the popper brands in our study, our results seem to support other studies’ findings that popper brands differ in quality and purity. In our case, labeling on all popper samples claimed the contents were pure isobutyl nitrite; however, H1 and C13 spectra indicated that this was not the case. Though isobutyl nitrite appeared to be present in our samples, we saw clear spectral deviations between the isobutyl nitrite control and all samples. Further, spectral differences between our samples suggest that the contamination profile varied between popper brands. In our case, this conclusion was evident even before beginning the NMR analysis. During sample preparation, some (but not all) popper brands formed a white precipitate when mixed with the CDCl3 vehicle, supporting the conclusion that brands differed in composition, quality, and purity. Assuming the precipitation reaction we observed reached completion (based on the 1:4 dilution ratio), our removal of the precipitates prior to NMR spectroscopy likely eliminated impurities that would have otherwise shown up in the sample spectra.

As other studies have noted, the impurities present in poppers are at best a mix of different alkyl nitrite species and their decomposition products and at worst contain toxic impurities [14,17]. The chemical shifts and coupling patterns seen in the spectra of our study samples may correspond to unreacted reagents used in the production of alkyl nitrites, the decomposition products of alkyl nitrites, additional alkyl nitrite species, unlisted preservatives, or otherwise unidentifiable contaminants. Given the diversity of spectra seen in our study, it seems likely that the impurities we observed represent contamination from multiple chemical sources. Even if the hazard of contamination is ignored, isobutyl nitrite is a known irritant with potential genotoxic, neurotoxic, carcinogenic, and immunosuppressive effects that may threaten users’ health [34,35].

The regulatory framework around alkyl nitrites has also contributed to the potential dangers of recreational popper use. The original popper, amyl nitrite, has the most evidence demonstrating its safety, yet it remains the most highly restricted alkyl nitrite [9]. Regulation has not deterred users, and poppers continue to be some of the most widely used recreational substances [5,6]. Instead, regulation has shifted production toward alkyl nitrite compounds with fewer legal restrictions [14], despite evidence suggesting they may be more likely to cause harm [8,12,34]. The counterintuitive effect this kind of regulation has on the safety of recreational popper use has previously been demonstrated in the United Kingdom, which outlawed the production and sale of isobutyl nitrite in 2007. However, other alkyl nitrite compounds, like isopropyl nitrite, quickly gained popularity to circumvent this regulation, with the end result being an increase in alkyl nitrite-associated morbidity [11,20].

The spurious legal status of alkyl nitrites has undoubtedly contributed to the risks associated with their use. Today, various alkyl nitrite compounds remain legal so long as they are not sold for human consumption [8,11]. In the United States, isobutyl nitrite poppers are widely available and are marketed as solvents, oderizers, or cleaners, albeit with packaging that is suggestive of their use as an inhalant [4]. Given the manufacture and sale of modern poppers as industrial chemicals, there is a distinct lack of incentive for producers to ensure the purity of their product or include appropriate warning labels and directions for safe usage and dosing. Regarding the poppers analyzed in this study, the contrast between the advertised use (e.g., clock cleaner, solvent cleaner, etc.) and the product name (e.g., “Ecstasy” or “Real Gold Poppers”) provides a compelling example of the incongruous way alkyl nitrites are regulated and marketed.

Within this convoluted legal and historical framework, there is ample room for misunderstanding on the part of users and poor quality control on the part of manufacturers. The original popper, amyl nitrite, has a long history—first as a prescription drug released in 1937 and then as a widely-used recreational substance available over the counter from 1960–1969 [9]. Though they share the same name, today’s poppers are composed of a different suite of alkyl nitrite compounds that are manufactured and sold under a very different set of regulations. Modern users may be unaware of these distinctions or how they impact the risks associated with recreational popper use.

Based on our chemical analysis of a small group of common popper brands, it appears recreational popper use may come with added exposure to a chemical not disclosed in marketing or on packaging labels. Similar to illicit street drugs, where the risk of impurities or contamination is understood, popper users should be aware that labels making claims about the purity of their alkyl nitrite contents cannot be taken at face value. Physicians who treat patients using poppers should also be aware of this potential problem and counsel patients accordingly. Just like other campaigns aimed at educating physicians about the role of toxic adulterants in illicit opioid and methamphetamine supplies, we suggest that clinicians who see patient populations with higher rates of popper use, such as MSM patients or those with a history of drug use, should be attentive to the risks posed by poppers [28].

4.1. Limitations

Unfortunately, elucidating the identity, relative concentration, or toxicologic effects of these contaminants was outside the scope of our investigation. Our analysis was also limited by our small sample size, representing only a handful of popper brands manufactured at a single point in time for sale within the US. We are unable to make any conclusions about the purity of all poppers currently on the market, especially those being manufactured and sold in countries with different regulations. Similarly, the spectra generated during our controlled experiment do not necessarily reflect what might have been detected under real-world conditions. Alkyl nitrites are reactive and volatile compounds, and their chemical degradation profile may differ when they are exposed to light, moisture, heat, or prolonged storage typical of recreational use. Lastly, because our analysis used an external control for comparison, we are unable to determine whether all the spectral heterogeneity in our samples is truly from contamination and not just artifacts of the spectroscopy. Still, with labels on all samples claiming the contents were pure isobutyl nitrite, differences in major chemical peaks across our samples is definitive evidence that most of our samples contained some impurities, and those impurities differed across brands.

4.2. Future Directions

In this study, we showed that popper marketing can be misleading and demonstrated that the purity of poppers should be questioned. While our analysis supports these general conclusions, the full scope of this problem is currently unclear. More research is needed to fully understand the chemical composition of recreational poppers, the identities of the common contaminants, and how they impact user health. Similarly, the current legal and regulatory framework around poppers may benefit from a re-evaluation. Given the popularity, accessibility, and relatively low-risk profile of alkyl nitrites, regulation based on a harm-reduction framework may be a valuable public health action [36]. Evidence-based policies aimed at protecting users, supporting public health, and educating clinicians should be prioritized when making decisions about how alkyl nitrites are regulated in the future.