Poppers

Poppers are a class of recreational drugs whose vapors are inhaled in "hits" to enhance sexual activity by causing smooth muscle relaxation and a rapid sensation of euphoria and warmth. Typically "poppers" refers to one of several alkyl nitrite compounds, though occasionally the term is incorrectly used to describe ethyl chloride or "spray poppers". Specific drugs in this class include compounds based upon amyl (n-pentyl) nitrite, isopropyl nitrite, and isobutyl nitrite, with variants or mixtures of multiple compounds in one formulation being common.

Poppers

Health risk	Moderate
Addiction risk	Mild
Legal risk	Mild
External links	PsychonautWiki Erowid

Background

Poppers, specifically amyl nitrite, were originally used as a prescription medication starting in the late 1800s to treat angina (chest pain). The term "poppers" originates from the original mode of distribution, in which amyl nitrite would be stored in small glass vials that could be broken (popped) to allow the vapors to be inhaled.

In the 1960s, a regulatory change waived the prescription requirements for amyl nitrite in the United States, and poppers gained popularity in the gay community for recreational use. In the 1990s, the availability of amyl nitrite was again restricted, which led to the other nitrite-based compounds being sold which were marketed as "room deodorizers" or "video head cleaner" to bypass these restrictions. For some time isobutyl nitrite was the most prevalent variant but in 2007, the EU banned isobutyl nitrite as a possible carcinogen, leading to isopropyl nitrite becoming the most common variant since.

Variants

Many alkyl nitrites have been synthesized for use as poppers. Broadly, these variants produce similar effects from vasodilation due to nitric oxide release. However, the chemical properties of each variant lead to slightly different characteristics, and may have different risk profiles.

Additionally, due to the unregulated and legally gray nature of poppers manufacturing and distribution, it is very difficult know what chemical(s) are contained in any given formulation of poppers with any certainty. While some poppers products list one or more alkyl nitrite ingredients on their labels, no independent verification of accuracy or purity is required. Additionally, poppers formulations may include additional unlisted chemicals as stabilizers or additives.

Variant	Vapour pressure (~25 °C)	Special considerations
Amyl (n-pentyl)	85.6 mmHg
Isoamyl (isopentyl)	~35-44 mmHg
	~62 mmHg @20 °C
Isobutyl	~10 mmHg @20 °C
	~342 mmHg
	~432-460 mmHg

Stability

All alkyl nitrites are inherently chemically unstable. Over time, even in ideal storage conditions, poppers can self-react and degrade into numerous byproducts, including alcohols, nitrous/nitric acids, and nitrogen oxides. These both reduce the desired effects, and can contribute additional undesired or harmful side effects if inhaled. Exposure to heat, moisture, light, and air greatly accelerate degradation. When poppers have considerably degraded, several changes may be observed, including: yellowing or browning of liquid, harsher acrid odor or fuming, or sticky or oily residues.

The ideal storage conditions are in an airtight, cold (<10 C), dark, and dry environment. Each time a bottle is opened, some amount of moisture is will be introduced from humidity in the air, which will accelerate degradation. Additionally, it may be best to allow poppers to warm to room temperature before opening them with each use to prevent condensation of more moisture inside of the bottle from the colder storage temperature.

Appeal

The appeal of poppers in a sexual context can vary from person to person, but some common reasons people use them include:

• Euphoria and Increased Sensation: Inhaling poppers can enhance sexual pleasure by causing rapid intense feeling of euphoria and increasing sensitivity to touch. For some, this can lead to heightened arousal and more intense orgasms.
• Reduced Inhibitions: Poppers can lower inhibitions and increase feelings of sexual openness and desire. This can lead to a more uninhibited and adventurous sexual experience.
• Enhanced Anal Sex: Poppers are particularly popular among individuals engaging in anal sex, as they can help relax the anal sphincter muscles, making penetration more comfortable and enjoyable.

Interactions

Poppers act synergistically with PDE5 inhibitors which are commonly used to treat erectile dysfunction. The combination of poppers and PDE5 inhibitors can cause dangerously low blood pressure with case reports of fatailities in the medical literature. Examples of PDE5 inhibitors include:

• Sildenafil (Viagra)
• Tadalafil (Cialis)
• Vardenafil (Levitra, Staxyn, Vivanza)

Risks

Systemic toxicity

When nitrite vapors are inhaled in a limited manner (i.e. a few hits during a scene), the risk of significant systemic toxicity is low (though other risks may still exist, see below). At high doses, nitrite compounds are highly toxic and can cause serious bodily harm or death.

Systemic toxicity from poppers is caused by a chemical reaction between poppers and hemoglobin (the substance in blood responsible for transporting oxygen from the lungs to the rest of the body). This reaction converts hemoglobin into methemoglobin (which cannot bind to oxygen), causing a condition called methemoglobinemia. When a considerable fraction of hemoglobin has been converted into methemoglobin (>20%), oxygen delivery to the body becomes significantly impaired, producing symptoms of organ dysfunction. At very high fractions (>40%), organ failure or death can occur. Methylene blue is an effective antidote which can rapidly convert methemoglobin back into hemoglobin, though this should always be administered by medical professionals in a hospital setting.

Note that many early signs of methemoglobinemia overlap with the direct effects of poppers. Cyanosis of the lips and digits is the most specific indicator.

Methemoglobin (% of total Hb)	Signs and symptoms	Risks
< 1%	Normal	None
1–3%	Normal in smokers.	None
5–10%	Usually no symptoms.	Minimal risk.
10–20%	Cyanosis (blue coloration) of lips, fingers, and toes. Minimal systemic symptoms.	Minimal risk in healthy individuals.
20–30%	Anxiety, headache, lightheadedness, increased heart and respiratory rate	Moderate risk. People with cardiovascular disease or anemia may require medical treatment.
30–40%	Fatigue, confusion, dizziness	High risk for organ damage. Medical treatment is required.
>40%	Seizures, coma, cardiac arrest	Life threatening emergency.

When a small amount of poppers vapors are inhaled, systemic toxicity is negligible as only a very small fraction of hemoglobin is converted into methemoglobin with each hit. Additionally, the body has the ability to completely reverse this reaction and restore functional hemoglobin, though this process can take hours or days (~1% of methemoglobin can be restored per hour). This has several important implications:

• If poppers use is ceased in a scene before truly dangerous levels of methemoglobin are formed, symptoms of mild methemoglobinemia should resolve over time without requiring medical treatment.
• With heavy sustained use in a longer scene, methemoglobin toxicity can become increasingly significant as the rate of methemoglobin formation will outpace the body's ability to clear it.
• Note that individuals with certain conditions such as cytochrome b₅ reductase deficiency or G6PD deficiency will clear methemoglobin much more slowly.

Dangerous high-dose exposure during recreational use typically occurs in one of two situations:

• Taking many hits repeatedly over a long scene. In this circumstance, signs and symptoms of toxicity will progressively develop, which can provide the opportunity for detection and cessation of use before serious harm develops. Blue coloration of lips, fingers, or toes is the most specific indicator that high levels of methemoglobin have accumulated, in which case poppers use should be immediately stopped in that scene.
• Ingestion of poppers in liquid form, in which organ failure and/or death can occur within minutes. Although data is limited, fatal case reports have been published for oral ingestion of amounts as small as 2-3 mL. Thus, the exposure of a nontrivial amount of liquid poppers into any body cavity (oral, nasal, rectal, etc.) should be treated as a medical emergency and emergency medical services should be called immediately.

Tissue burns

Exposure of bodily tissue to liquid poppers can cause chemical burns from oxidation.

• Exposed skin should be thoroughly but gently rinsed with water and mild soap.
• If the eyes are exposed, remove contact lenses and continuously irrigate with water for 15 minutes.
• Poppers can be absorbed through the skin or eyes, so with more significant exposure, monitor for signs of systemic toxicity.

Poppers retinopathy

Poppers use has been associated with a unique form of eye damage called poppers retinopathy (formerly poppers maculopathy). Although this condition is not completely understood, it is thought to be caused by hyperactivation of cones in the retina from high levels of nitric oxide released by poppers, which can cause retinal cell injury.

Some experts believe that poppers retinopathy most commonly occurs following a period regular use over months or years, in which small amounts of damage occur with each use and accumulate over time. However, cases in first-time users have also been reported, suggesting that the mechanism of injury can occur much more rapidly in some circumstances. The average age in which poppers retinopathy develops is around 40 years old, and patients with a longer history of poppers use had worse visual deficits initially, which both support the concept of accumulation of damage over time being a significant factor.

Symptoms

Most individuals with poppers retinopathy develop a region of visual impairment in the center of their vision, usually in both eyes. A common narrative describes the onset of a bright circle in the center of their vision (clinically called a "phosphene", informally described as a green or yellow "eye of sauron") during a session of poppers use. After the session, the bright quality of the spot fades, but their vision remains abnormal in that area for days to weeks. The degree of impairment reported varies, from mildly reduced visual acuity, blurry vision, to near-complete vision loss.

In some cases, there is clear evidence of retinal damage on a basic fundoscopic exam (taking high-resolution pictures of the surface of the retina). However, in others, a fundoscopic exam was normal, and evidence of damage could only be identified using a more sophisticated test called spectral domain optical coherence tomography (OCT).

Prognosis

With complete cessation of poppers use, most patients report subtantial improvement or full recovery of their vision over a period of several months.

Prevalence

Although the number of case reports in the medical literature is relatively small (~100), it is believed that the number of affected individuals is likely much higher. Many anecdotal reports can be found online from users on social media and message boards. Additionally, some people describe commonly develping a very similar bright spot in their vision during poppers use that completely resolves 5-15 minutes after the end of a scene. It is unknown if the transient phosphene seen during use is associated with the development of mild injury that could increase the risk of more substantial vision impairment in the future, or if some users are less prone to chronic injury.

Chemical variants

While it is likely true that any alkyl nitrite can lead to the development of poppers retinopathy, there is fairly strong evidence to suggest that isopropyl nitrite in particular may have elevated risk of causing this condition. One reason supporting this view is purely emperical. Reports of vision impairment from poppers use were extremely rare prior to 2007. This coincided with when the EU banned isobutyl nitrite due to being classified as a carcinogen, and many poppers formulations transitioned to use isopropyl nitrite. In the following years, the number of case reports of poppers retinopathy greatly increased, and in cases that tested the specific formulation used by the patient, isopropyl nitrite was identified in the vast majority of these reports.

However, case reports implicating both amyl nitrite and isobutyl nitrite as causing vision loss exist, and anecdotal reports of isobutyl nitrite producing a similar phosphene during use online are common. One possible explanation for why isopropyl nitrite may be especially hazardous to cause this condition is that is it considerably more volatile than either amyl or butyl nitrites, which would allow much higher doses to be inhaled in a short period of time and cause much higher transient partial pressures in the blood with each hit. If there is a dose-dependence to this toxic mechanism, it could explain why so many more case reports are associated with isopropyl nitrite specifically, and especially why damage from a single use is now being reported.

Cancer risk

Poppers are oxidizing agents which inherently induce some degree of oxidative stress in body tissues. Isobutyl nitrite is the only specific compound which has been identified by International Agency for Research on Cancer (IARC) as "possibly carcinogenic to humans" (group 2B). For this reason, isobutyl nitrite has been banned in the EU since 2007.

However, a proposed mechanism for the carcinogenicity of isobutyl nitrite would reasonably apply to all alkyl nitrites (alkyl nitrites react with amines in acidic environments to form nitrosamines which are known carcinogens).

Fire

All alkyl nitrite poppers are highly flammable and vapor-air mixtures can explode in confined spaces if heated. The exact temperature at which autoignition occurs varies depending on the chemical variant.

Odor

If spilled in on absorbent surfaces like funiature or carpet, a strong poppers odor can persist for long periods of time and may require professional cleaning or replacement to resolve.

Risk mitigation

• Limit the total dose used in a scene to a relatively small number of hits
• Limit the risk of spills or direct bodily exposure to poppers liquid
  • Specialized equipment (e.g. "sniffers") is available which can help prevent leaks even when the bottle is tipped.
  • Transfer a small amount of poppers liquid onto a disposable absorbent material like cotton or a paper towel in a separate bottle or inhaler.
  • Store bottles with tightly closed lids on stable surfaces.

• Stop using poppers in a scene immediately if
  • Blue lips or nail beds are observed in the user
  • A phosphene (i.e. a bright spot, often green or yellow "eye of Sauron") develops in the center of vision

• Pulse oximetry may not be reliable due to confounding from methemoglobin with heavier use in a scene. Some pulse oximeters are capable of differentiating hemoglobin and methemoglobin, but this is less common in consumer grade pulse oximeters.

Known incidents

Medical case reports

• 23yr old male in the ER with hypoxemia, methemoglobinemia, and syncope (2023)
• 39yr old male in the ER with hypoxemia and methemoglobinemia (2012)
• 55yr old male in the ER with hypoxemia and methemoglobinemia for over a day (2016)
• 44yr old male in the ER with hypoxemia, methemoglobinemia, unresponsive, stopped heart (1995)
• 34yr old male in the ER with hypoxemia and methemoglobinemia for 4 days (2012)
• 12 cases of impared vision presenting to an eye hospital (2017)

External links

• https://psychonautwiki.org/wiki/Poppers
• https://trikoot.net/2017/01/poppers-eye-damage-and-maculopathy/
• https://trikoot.net/2018/01/faq-poppers-and-eye-damage/
• https://trikoot.net/2020/11/poppers-and-viagra-the-history-and-science-of-the-dangerous-cocktail/