High-sight: eyeing unanticipated effects of a ‘harmless’ drug

By Sarah Roche

After a long night of partying, Ivan* found himself staring at his reflection in the mirror. Still somewhat intoxicated he didn’t fully comprehend what he saw, or rather, what he did not see: Where his own face should have been staring back at him, he saw a large black void, a sphere of darkness in the center of his visual field. “There was nothing there, I looked at my face and couldn’t see [it]. It was a very…strange and terrifying experience,” Ivan recalled while sharing this memory. In a state of uncertainty and concern, he went to sleep, assuming everything would be back to normal in the morning. But he was wrong.

Like so many other partygoers across Europe, Ivan had used a drug known as “poppers” the night he lost part of his vision. Poppers are a form of volatile alkyl nitrite, compounds that release nitric oxide in the body leading to smooth muscle relaxation, increased heart rate, and vasodilation¹. Alkyl nitrites were originally used as a therapeutic treatment for cardiovascular disorders such as angina, but have since become a popular recreational drug². 

Ivan isn’t a frequent poppers-user, and he only knew that the drug was mildly euphoric and widely regarded as a safe substance. However, when he awoke the next morning and found that his vision had not improved, he went looking for answers.

Ivan quickly learned that poppers are not as innocuous as their reputation suggests

In his search for an explanation for his altered vision, Ivan learned that poppers have been part of the club-drug repertoire for decades, widely believed to be a low risk substance³. Although the consumption of poppers is not officially legal, production and sale of the substance is without restriction, as long as they are advertised for uses such as air fresheners, cleaning agents and nail polish remover^4,5. But as he worked his way through the literature, Ivan found a shift in reporting on the safety of recreational use of alkyl nitrites that coincides with a 2006 directive of the European Union⁶ , banning the commercial use of isobutyl nitrite (C₄H₉NO₂), the main ingredient in poppers. 

In light of the ban on isobutyl nitrite, poppers suppliers have since substituted the chemical with a compound that differs in its formula by only one fewer carbon group: isopropyl nitrite (C₃H₇NO₂). Ever since the change in the poppers formula, there have been a small, yet significant number of reported cases of poppers-induced maculopathy; a loss of visual acuity caused by retinal damage⁴. Ivan had his answer.

Fleeting highs, permanent damage

Retinal degeneration has long been a central focus of ophthalmic research, but treatments to promote the reversal of this process have proven to be elusive, owing to the fact that the retina is composed of neural cells which have a low propensity for regeneration and repair. So, for many people who experience maculopathy, the effects are permanent. Thus, the recent rise in maculopathy cases reported among poppers users should raise public health concern, and yet the issue has not been widely addressed in the media, and the majority of available information either comes from anecdotal accounts or individual case studies⁷.

There is only one study currently in existence that has attempted to compile the available case reports to elucidate the level of risk of poppers-induced maculopathy. From an analysis of a survey on recent poppers-users from North America, Australia, the UK and Europe, 87.8% of individuals reported no vision problems, 10% believed they might have developed vision issues, and 2.2% of users self-reported definitive poppers-associated vision loss⁴. In total, only 50 cases of loss of visual acuity after poppers use have been reported as of 2016, however the authors of this study argue that this is a significant enough cause for public health concern⁴.

While it is becoming evident that poppers may pose a risk to users’ health, it isn’t completely clear why the adaptation to the poppers formula is causing retinal damage. Some researchers suggest that recent advances in technology make maculopathy easier to detect, leading to an increase in diagnosed cases, not necessarily an effect of the new poppers recipe⁴. Pinning poppers as the culprit is further complicated by the fact that volatile alkyl nitrites, and inhalants in general, are a relatively understudied drugs of abuse⁸ and not much is known about their mechanism of action. Despite reports of a sense of euphoria when consumed, whether or not these substances are psychotropic also remains a subject for debate⁸ contributing to the relatively relaxed control of their use⁵. However, some studies have shown that alkyl nitrites indeed influence cognition, implicating them in deficits of learning, memory and coordination⁹. This suggests that poppers are potentially neurotoxic, and perhaps a similar mechanism is affecting both the brain and retinal cells in some individuals.

The eye-popping effects of volatile alkyl nitrites

What exactly is happening in the retina when someone uses poppers? At this point, scientists aren’t sure, but they have proposed a few possibilities. One popular hypothesis is that when someone inhales poppers, nitric oxide is released in various regions within the body, including the retina of the eye. Nitric oxide appears to have a particularly strong interaction with light-detecting cells in the eye called photoreceptors, interfering with the phototransduction cycle**. This is the process through which incoming light information is converted into electrical and chemical signals that are eventually interpreted by the visual cortex in the brain, allowing us to build our visual precept of the world around us.

In order for us to continue visualizing our world, this phototransduction cascade needs to occur over and over again in sequence. The cycle can only continue when photoreceptor cells are “reset” from a temporary refractory period by a protein called guanylate cyclase (GC). Without GC, the signal cascade cannot continue, and vision is disrupted¹⁰. It is thought that the acute increase in nitric oxide concentration following poppers inhalation leads to an interaction between nitric oxide and GC, disrupting the phototransduction cycle, and affecting photoreceptor metabolism in a manner that could be toxic to the cells^1,7,11. Despite evidence to support these claims, there is no definitive proof suggesting that the interaction between nitric oxide and GC is responsible for poppers-induced maculopathy, and it’s still unclear how the switch from isobutyl- to isopropyl nitrite might be contributing to retinal damage.

Losing sight of safety regulations

Regardless of the uncertainty surrounding the physiological basis for poppers-induced maculopathy, one thing is certain: the drug has the potential to pose a health risk to users and the current steps in place to regulate the use and production of these compounds are doing nothing to ameliorate the problem. As recently as 2016, the ACMD has re-evaluated the status of poppers, declaring them neither psychotropic nor especially dangerous. This stance is surprising given that, according to the 2016 poppers use survey study, while 27% of poppers users reported an improvement in their vision after cessation of use, 12% reported that their visual deficits have persisted and 4% reported even further decline in visual acuity⁴. These statistics do suggest that there is hope for recovery among poppers users who have experienced visual impairment, however, the possibility of sustained or permanent effects suggests that the potential risks associated with poppers use should be more widely disseminated.

As for Ivan, it’s been more than a year since he first experienced vision loss after using poppers. Since then, his vision has improved and he no longer has a noticeable blindspot, which he attributes to slight recovery of the retina as well as some degree of compensation for the loss of light detection. Though he still notices some slight deficits in his vision, Ivan feels like things are back to normal for him. “I was getting used to the idea that I was going to live with this forever,” he shared, “I wouldn’t say it’s 100% healed, but…it doesn’t affect me in any way.” He says that the experience opened his eyes to the less obvious risks that come with drug use, a message he hopes to spread by sharing his story, ensuring that his frightening experience was not in vain. 

*name changed to maintain anonymity of source.

**For a short video about the phototransduction process follow this link.

References

1. Krilis M, Thompson J, Atik A, Lusthaus J, Jankelowitz S. 2013. ‘Popper’-induced vision loss. Drug and Alcohol Review;32:333-334.

2. Sigell LT, Kapp FT, Fusaro GA, Nelson ED, Falck RS. 1978. Popping and snorting volatile nitrites: A current fad for getting high. Am J Psychiatry; 135(10):1216-1218.

3. Nutt D, King AL, Saulsbury W, Blakemore C. 2007. Development of a rational scale to assess the harm of drugs of potential misuse. Health Policy;369:1047-1053.

4. Davies AJ, Borschmann R, Kelly SP, Ramsey J, Ferris J, Winstock AR. 2016. The prevalence of visual symptoms in poppers users: a global survey. BMJ Open Ophthalmology, 1:1-6.

5. Iverson L, May T, Hunt J, Ellison J. 2016. ACMD review of alkyl nitrites (“poppers”). Advisory Council on the Misuse of Drugs. Obtained from link.

6. Directive 2005/90/EC of the European Parliament and of the Council. 2006. Official Journal of the European Union. Obtained from link.

7. Vignal-Clermont C.2010.Poppers-associated retinal toxicity. The New England Journal of Medicine; 363:1583-1585.

8. Beckley JT and Woodward JJ. 2013. Volatile solvents as drugs of abuse: focus on the cortico-mesolimbic circuitry. Neuropsychopharmacology;38:2555-2567.

9. Cha HJ, Kin Y J, Jeon SY, Kin YH, Shin J, Yun J, Han K, Parak H-K, Kim HS. 2016. Neurotoxicity induced by alkyl nitrites: impairment in learning/memory and motor coordination. Neuroscience Letters; 619:79-85.

10. Holmes D. 2018. Reconstructing the retina. Nature;561,S2-S3.

11. Goldstein IM, Ostwald P, Roth S. 1996. Nitric oxide: a review of its role in retinal function and disease. Vision res; 36(18):2979-2994
    

Title image based on art by Phillip Blackman. All other images were custom-made using bioRender.

About the author

Sarah is a second year Neurasmus student who is completing her MSc in neuroscience with an interest in addiction, motivation and decision making. Outside of research she enjoys both scientific and creative writing, sketching, painting and cycling, and is still dreaming of a career that allows her to incorporate all of those activities.