- - I - I- I M Nitrite Inhalants: History, Epidemiology, and Nitrite 'in'alat's have been commonly :abused sR e&insla the nIted tates. Possible Links to AIDS Nitre ixa m s a npopular topic in the early 1980sX tecu of Harry W Haverkos, Andrea N. Kopstein,1 Hank Wilson, and Peter Drotman3 AIDSWas not k Wn.Withthe discovery of 1National Institute on Drug Abuse, Rockville, MD 20857, USA; 2Committee to Monitor HIV, concern about nitrite use in the USA Poppers, San Francisco, CA 94102 USA; and 3National Center for Infectious Diseases, waned. However nitrite inhalant use is Centers for Disease Control and Prevention, Atlanta, GA 30333 USA asoiae wit baaiorl reaaeadt.t.n.mX.g......w...`n ad.`HgaZ..HWnWl t dKcre£'.L''p te. cn. an natural Nitrite inhalants are commonly abused the package insert is angina pectoris (17). killer cel activity in a few labitory stud- substances in the United States, primarily Amyl nitrite is used experimentally to treat ies, d t:r a c ec tor in by homosexual men and others who use cyanide poisoning. The drug produces the patdge-nesis of AIbS-rele Kaposi's nitrites to facilitate sexual intercourse methemoglobin, which has a high affinity sarcomia. Discourap g ir :continues and/or produce euphoria (1-4). Scientific for cyanide, and leads to the production of to be a wordiwhll&pubiic healthjI.il Key in o.rd: AD5 HI infection' Inimunosup- interest nitrites increased in the 1980s cyanomethemoglobin, releasing cyanide pressio.... Kpoi's. sarcoma, nitrite due to their possible links to AIDS (5-11). from cell mitochondrial cytochrome oxidase ;$ ir behaor. Envmn Health In this paper we review the history, appli- sites, where it is otherwise destructive (18). Perspect 102:858-861 (1994) cations, and prevalence of use of nitrite When amyl nitrite became difficult to inhalants. We present the hypotheses link- procure for nonmedical or recreational pur- ing their use to AIDS. We provide sugges- poses during the 1970s, there was a prolif- mia, intoxication, and, rarely, death (15). tions to physicians, community leaders, eration of butyl nitrite products by non- Other effects include development of policymakers, and researchers on what they pharmaceutical manufacturers (15). Butyl habitual use patterns, tolerance, and burns can do to limit the use of nitrites. nitrites were marketed as "liquid incense" resulting from inadvertent ignition of the or "room odorizers." Because the labels on vapor. The National Toxicology Program History and Clinical Uses bottles containing butyl nitrites stated that of the National Institute of Environmental The alkyl nitrites (e.g., amyl, butyl, iso- they were not to be inhaled and no health Health Sciences evaluated mice and rats propyl) are colorless or yellow liquids at claim was made, the FDA never had juris- exposed short term (6 hr/day for 14 days room temperature and are highly volatile. diction over this product as it does medi- and 13 weeks) to inhaled isobutyl nitrite at They are esters of nitrous acid that have a cine and many foods. concentrations ranging from 0 to 800 ppm fruity odor (often described as unpleasant) The legal status of some key nitrite and noted several adverse effects. Rats and have been nicknamed "poppers" because preparations has changed in the past few exposed to greater than 600 ppm died dur- of the sound made when glass capsules con- years. One development prompting this ing the 14-day studies. At lower exposure taining amyl nitrite are crushed (12). change has been the description of several levels, the most striking lesion seen in mice The vasodilatory effect following acute and chronic adverse effects attributed was hyperplasia of the nasal mucosa and inhalation of amyl nitrite vapor was to the abuse of nitrite inhalants (15). In bronchial and bronchiolar tree. described in 1859 and led to the first response to those reports, the U.S. Methemoglobinemia was confirmed. report of its clinical application to provide Congress enacted a ban on the manufac- Other adversely affected organs included relief for angina pectoris in 1867 (13,14). ture and retail sale of butyl nitrites (except the liver, spleen, thymus, and bone mar- In the 1880s, butyl nitrites were found to when used in specified chemical commer- row (19). have similar vasodilatory qualities, but cial processes) in the Anti-Drug Abuse Act these compounds were never developed for of 1988 (Public Law 100-690, Section Prevalence ofNonmedical Nitrite Use clinical use (12). 2404). The law specified that the Con- Alkyl nitrites are among the most com- Amyl nitrite was initially marketed as a sumer Product Safety Commission (not the monly used inhalants in the United States. prescription drug in the United States in FDA) would enforce the ban. However, to Other commonly abused inhalants are 1937 and remained a prescription drug circumvent the clear intent of the law, nitrous oxide, gasoline, glues, and solvents, until September 1960, when the Food and nitrite manufacturers began to sell other such as paint thinners. The National Drug Administration (FDA) eliminated nitrite alkyl congeners, such as isopropyl Institute on Drug Abuse has collected the prescription requirement. In the 1960s, nitrite, as "new and improved" room odor- information concerning nitrite inhalant nitroglycerin sublingual tablets, dermally izers. In 1990, Congress outlawed manu- use among high school seniors since 1979. applied ointments, and, later, transdermal facture and sale of alkyl nitrites in the Eleven percent of high school seniors patches began to replace amyl nitrite as the Omnibus Crime Bill (Public Law 101-647, interviewed in 1979 reported ever using preferred treatment for angina pectoris. In Section 3202). Since then, at least one nitrites. Use has decreased consistently the late 1960s, pharmacists and drug man- manufacturer has developed a cyclohexyl among seniors since 1980, to 1.5% for the ufacturers noticed widespread purchases of nitrite inhalant and marketed it diversely. class of 1992 (20). amyl nitrite by apparently healthy young According to chemical nomenclature, According to national surveys, self- men. These over-the-counter purchases cyclohexyl nitrites are not in the same class reported amyl and butyl nitrite use varies became the impetus for the FDA to rein- as alkyl nitrites and therefore may not be by gender, region, and race. Male high state the prescription requirement in 1968. banned under current federal law. school seniors reported higher rates of Since then an underground market for Underground manufacturers and importers amyl nitrite has emerged (15). For the last continue to market butyl and isopropyl few years, there has been no medical adver- nitrites illegally. Address correspondence to H. W. Haverkos, tising for pharmaceutical-grade amyl nitrite, The acute toxicity of inhaled and Room 1OA-38, NIDA, 5600 Fishers Lane, Rockville, MD 20857 USA. and it is no longer listed in the Physician's ingested nitrites in humans includes skin We thank Peter Delany, William Grace, and Desk Reference (16). irritations (especially around the nose and Vincent Smeriglio for reviewing the paper and Amyl nitrite remains available by pre- lips), tracheobronchial irritation, headache, providing helpful comments. scription. The clinical indication listed in hypotension, cyanosis, methemoglobine- Received 2 June 1994; accepted 25 July 1994. 858 Environmental Health Perspectives I .. s i 1i 1ifi S M M Mfi&EF1diJIl1&-fj- A g-. inhalant use and nitrite use than females. heterosexual men and women who did not day for 3 or 18 days on the immune sys- The proportion of males who used nitrites consistently report using nitrites. In 1983 tems of 18 male volunteers. One inhala- at least once was typically twice the per- and 1984, human immunodeficiency virus tion of amyl nitrite (0.18, 0.36, or 0.48 centage of females reporting lifetime use (HIV) was discovered and reported as the ml) was administered from a closed 4-1 (20). The highest rate of nitrite use report- cause of AIDS (31,32). Subsequently, flask at 3-hr intervals each day of study. ed by high school seniors in 1979 was in three other hypotheses suggesting nitrites After full exhalation, the subject inhaled the Northeast, and the lowest rate was as promoting factors in AIDS have been from the flask through the mouthpiece reported in the West. Rates have decreased proposed. First, nitrites have been pro- with the nose "clipped" and held at full markedly in all regions, with the highest posed to enhance HIV transmission by inspiration for 5 sec before exhalation. rates in 1992 reported in the North- their association with risky sexual behaviors Blood was drawn for immune profile Central United States and the lowest rates and HIV infection among gay men. immediately after the last inhalation and 1, in the Northeast (21). Second, nitrite use has been associated 4, and 7 days later. Modest depression of Nitrite use varies by race/ethnicity as with immune suppression and thus might T-lymphocyte counts and natural killer cell well as geographic area. Although hasten the onset of symptomatic disease. activity were noted with a rebound to at racial/ethnic data are not available for high Third, nitrite inhalant use has been associ- least baseline levels several days after the school seniors, the Public Health Service- ated with the development ofAIDS-related last inhalations. Cell proliferation respons- sponsored National Household Survey Kaposi's sarcoma. es to phytohemagglutinin (PHA), con- provides limited population-based esti- Nitrites and Sexual Behavior/HIV canavalin A (Con A), and pokeweed mito- mates. Self-reported nitrite use in 1991 was Transmission. Several studies have linked gen (PWM) were unaffected by amyl highest for white males in each of six nitrite use with risky sexual behavior nitrite inhalation (36). selected metropolitan areas for which data and/or HIV infection among gay men. Ross and Drew (37) interviewed 97 gay were analyzable.