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Poppers

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Alkyl nitrites are a group of organic compounds with the general formula R-O-N=O, where R is any organic group. Amyl nitrite has historically been used for the treatment of angina, among other legitimate medicinal uses. Other alkyl nitrites, including butyl nitrite, isobutyl nitrite, isopropyl nitrite, ethyl nitrite, methyl nitrite as well as the disputed cyclohexyl nitrite, have been widely used for 40 years as the primary ingredients in room odorizer products and as recreational drug. The vapours of the alkyl nitrite are inhaled directly from the bottle, inducing an almost-instant, euphoric head rush; the body's smooth muscle, such as the sphincter, is relaxed. As a recreational drug, they are primarily used to enhance the sexual experience.

Basics

Cyclohexyl nitrite, butyl nitrite, isobutyl nitrite, and other light alkyl nitrites can be found as the primary ingredient in so-called 'room odorizers,' despite the malodorous nature of some of these compounds. These products are traditionally marketed in small glass bottles that, like amyl nitrite capsules, are referred to as poppers. Nitrite-based odorizers are available in adult bookstores and shops and over the Internet, and are regulated by a variety of federal and local regulations and legal restrictions, though the status of cyclohexyl nitrite — technically not a member of the class of alkyl nitrites encompassed by the law — remains in question in the United States, as a result of the controversial Federal Analog Act.

The alkyl nitrite which has been used medicinally, amyl nitrite (pentyl nitrite), was popularized in Hunter S. Thompson's Fear and Loathing in Las Vegas. Other popular nitrites include isopropyl nitrite, isobutyl nitrite, butyl nitrite and cyclohexyl nitrite.

The two main vessels for alkyl nitrites are small glass vials/bottles ("freshness jars"), or small ampules which are popped or snapped in order to release the vapors. The name snappers is sometimes used. The vials are simply uncapped, and the vapours are inhaled. The ampules contain small amounts of the alkyl nitrite, and are enough for only a few doses; while the vials contain enough of the alkyl nitrite for hundreds of doses.

Users

Poppers are often found in usage by homosexual men, but usage is reportedly popular among straight men and women as well. These products are generally used in an attempt to enhance the sexual experience. The existence of poppers became more widely known to the layman when they appeared in Radley Metzger's cult classic film Score (1972). In the film, a bisexual woman glides them under the nose of a heterosexual woman in an attempt to loosen her vagina for seduction. During the 1970's and 1980's, the mainstream media widely reported on the use of nitrite odorizers.

The alkyl nitrites relax smooth muscle, which is what the sphincter muscles of the body are comprised of (included in the sphincter muscle group are the anus and the vagina). Anectdotal evidence reveals that men and women, both, often find the experience of using poppers pleasurable. Homosexual men are a marketing target for "Poppers," since the alkyl nitrites help relax the muscles of the anus, allowing easier penetration and enhanced sensation. In addition, they are widely reported to greatly enhance and prolong orgasms. Ironically, some men find that poppers interfere with the ability to maintain an erection, if used to excess.

Nitrite users — who tend to be adults rather than adolescents as are most other inhalant users — seek to enhance the sexual experience. Inhaled nitrites dilate blood vessels, increase heart rate, and produce a sensation of heat and excitement that can last for several minutes.

They are also inhaled by users of other recreational drugs to enhance the effects, for example Ecstasy, the effects of which combine with those of Nitrites to produce an extremely intense rush of euphoria and physical pleasure. Since the rise of Acid House in the late 1980s Nitrites have become a large part of rave culture, used on the dance floor to heighten the experience of music and lights.

Chemistry

Alkyl nitrites can be synthesized from primary alcohols according to the following reaction process:

R-OH + NaNO2 + H2SO4 ==> R-ONO + NaHSO4 + H2O

It has been reported (US Patent 4,638,094) that alkyl nitrites are also a precursor for MDP2P, a phenylacetone used in the production of MDMA, more commonly known as "ecstasy." The basic reaction process is shown below:

MeONO in corresponding alcohol + safrole + PdCl2 [+ CuCl2 or amine ] ==> MDP2P

Health hazards

Apart from the Kaposi's sarcoma controversy (see below), there are a number of negative health effects caused by poppers. Alkyl nitrites were shown to be immunosuppressive, mutagenic and carcinogenic in animals and humans (see the reference section for details). They cause a short-term methemoglobinemia leading to a serious lack of oxygen in the brain for about a minute which is the base of the Poppers rush. High doses of Nitrites may also cause long-term methemoglobinemia, particularly in individuals predisposed towards such a condition.[1]. Use with viagra can cause heart failure, and individuals with anaemia or heart, breathing or blood pressure conditions may be at risk of complications. Since pressure in the eye and cranium is increased, individuals with glaucoma or traumatic head injuries may be have an added risk of negative short term and long term effects.

According to the National Institute on Drug Abuse, use of these drugs is associated with unsafe sexual practices that increase the risk of contracting and spreading infectious diseases such as HIV/AIDS and hepatitis.[2] A short-term immunosuppressive effect has been observed in mice as well as in humans; regular use of the drug over years may lead to an irreversible suppression of the immune system.[3]

Poppers users also run the risk of developing a psychological dependence to the drug, and tolerance may increase with use [4], [5], [6], [7].

Alkyl nitrites can burn the skin on contact, and may be fatal if swallowed or injected. It is also usual for usage to be associated with extreme headaches.

In the earliest days, around the time the AIDS crisis was unfolding, TIME Magazine reported that the poppers industry was grossing over $50 million a year and was the main financial support of the gay press through advertising. In 1983, after a meeting between the CDC's principle AIDS investigator, James Curran and Joseph Miller, president of Great Lakes Products, the manufacturers of popular nitrite brands such as RUSH, Miller claimed that poppers had been exonerated by the Center for Disease Control; James Curran of the CDC was quick to reply that he had been misinterpreted by Miller, but the gay press failed to publicize his response. He also stated that:

Other health hazards (than AIDS) from misuse of these drugs have been documented. Your press release and advertisements in the Advocate are misleading and misrepresent the CDC findings and their implications... While it is unlikely that nitrites will be implicated as the primary cause of AIDS, their role as a co-factor in some of the illnesses found in this syndrome has not been ruled out. I must insist that you discontinue the misuse and misinterpretation of CDC findings.
Letter from James Curran to Joseph Miller, September 27, 1983

Kaposi's Sarcoma controversy

The possible hazards of nitrite use has been a contentious issue since their introduction; in particular, a possible link between nitrites and AIDS and AIDS related illnesses, both of which have long been hotly disputed.

In particular, an argument is often made connecting Kaposi's sarcoma, a rare form of cancer, with poppers use. A minority of scientists, including HIV/AIDS denialist Peter Duesberg, suggest the existence of a link between the two. These scientists argue that Kaposi's sarcoma occurs in homosexual AIDS-patients 20 times more often than in non-homosexual AIDS-patients, and that therefore some cofactor must be involved beyond the virus HIV itself. Poppers have been suggested as a candidate for that cofactor, especially in view of the fact that they have been shown to be carcinogenic (the scientific results about the carcinogenicity were obtained in the same way as for medical drugs, see the reference section). the large MACS study in 1987 concluded that no such connection with poppers exists.However, a 1993 MACS publication(PMID 835696) found nitrite inhalant use a significant risk factor for KS.In 2002, Casper (PMID 11920325), found that poppers use was an independent risk factor for HHV-8 seroconversion. In 2000, Pauk et al. (PMID 11070101) found amyl nitrite use an independent risk factor for HHV-8 infection. It is now suspected that HHV-8,a member of the herpes family, is a co-factor for Kaposi's sarcoma. However, HHV-8 does not usually progress to Kaposi's sarcoma. Research continues to explore risks for the transmission of HHV-8 and the progression to Kaposi's sarcoma. Research findings have been inconsistent ,(Haverkos and Drotman, PMID 7744258) cite 5 published studies finding a correlation between KS and poppers use and point out that differences in research methodologies may account for some of the discrepancies

Medical uses

Alkyl nitrites were formerly clinically utilized as a vasodilator in order to treat angina, and as part of the treatment regimen for cyanide poisoning. Because of their side effects and unreliability, they were replaced by Glyceryl trinitrate in cardiology.

Disclaimers of manufacturers

In an apparent effort to circumvent laws against the sale of drugs/pharmaceuticles, poppers manufacturers often use disclaimers, ranging from mild warnings:

Note: All our nitrite based products are sold as room odorants, liquid incense, liquid aromas, or video head cleaner only. Although research indicates it is generally safe to do so, we do not encourage the misuse of our products as poppers. We are not responsible for the media claims that liquid aromas or poppers are said to be aphrodisiacs or sex drugs, and we do not endorse such claims. Our products do not contain amyl nitrite or butyl nitrite. They contain highly pure isobutyl nitrite, alkyl nitrites, cyclohexyl nitrite or hexyl nitrites only (taken from a company website [8])

to a more strongly worded disclaimer by a Florida USA website selling these products:

These room odorizers, liquid aromas, and incense are NOT for human consumption. They are room odorizers, leather cleaners, adhesive removers, etc. and should only be used in strict accordance to the manufacturers' instructions. "Not for human consumption" means you should not put them in your nose, mouth, eyes, or anywhere else in or on your body. Severe Eye Irritant: In case of eye contact flush with lots of water. Very Harmful if Swallowed. Do Not Inhale: Use only in large, well ventilated, open rooms. We prohibit sales to anyone who indicates to us they intend to abuse these products in any way. MANY Products are industrial cleaners and are therefore flammable: Do not use near fire or flame. You Could Die: The abuse of these products can kill you. Please use common sense when using these odorizers, aromas, cleaners and incense. Use of these products with Viagra can be fatal. Buyer assumes all risks and liabilities with the use of these products and holds [...], it's [sic] owners, employees, and contractors harmless. Note: All our nitrite based products are sold as room odorants, liquid incense, liquid aroma, or video head cleaner only. Our products do not contain amyl nitrite or butyl nitrite. They contain highly pure isobutyl nitrite, alkyl nitrites, cyclohexyl nitrite or hexyl nitrites only. [9] (emphasis added)

Historical aspects

It is a widely shared sentiment that street drugs like Poppers, Amphetamines, Crystal Meth destroyed the gay movement and culture and turned them into what's nowadays called the "gay scene" (see Ian Young: The Stonewall Experiment ISBN 0304332720). More than half the gays in industrialized countries take at least one of those drugs (PMID 11784456, PMID 11707675, PMID 12400463, PMID 15265096, PMID 15511735, PMID 12717048). That's considered the result of the efforts of street drug producers, vendors, pushers and the whole street drug milieu which infiltrated the gay movement. The process is quite analogous to what happened to the Black liberation movement in the Black ghettoes when Crack was introduced and to the Hippies and the civil rights movement of the 60s when Heroin was made ubiquitious.

Street names

(NOTE: Street names for these products include names that are actual brand names. For example, RUSH® and Locker Room®, the original nitrite aromas, and Liquid Gold™, a brand from England, are all registered trade names of actual popper brands.)

  • Poppers
  • Amyls
  • Snappers
  • Locker Room®
  • RUSH®
  • Liquid Gold™

References

Alkyl nitrites were shown to be immunosuppressive, mutagenic and carcinogenic in animals and humans. This is a generally accepted fact that is independent of the controversy about Poppers being a cofactor for AIDS and Kaposi's sarcoma.

  • Tran DC, Brazeau DA, Nickerson PA, Fung HL (2005), Effects of repeated in vivo inhalant nitrite exposure on gene expression in mouse liver and lungs., Nitric Oxide. PMID 16288974
"Exposure to inhalant organic nitrites (drugs of abuse commonly known as "poppers") has been reported to enhance tumor growth in mice, but the mechanism is not fully defined. [...] In conclusion, multiple exposures to inhalant nitrite appeared to cause alteration in the expression of a number of genes relating to cancer and angiogenesis, including VEGF. [...] These studies demonstrate that in vivo exposure to inhalant nitrites results in changes in the angiogenesis cascade."
  • Soderberg LS, et al. (2004) "Production of macrophages IL-1beta was inhibited both at the levels of transcription and maturation caspase-1 following inhalation exposure to isobutyl nitrite." Toxicology Letters 2004 Aug 30; 152(1):47-56. PMID 15294346.
  • Ponnappan U, et al. (2004)"Inhaled isobutyl nitrite inhibited macrophage inducible nitric oxide by blocking NFKappaB signalling and promoting degradation of inducible nitric oxide synthase-2." Int. Immunopharmacology 2004 August; 4(8):1075-82. PMID 15222982.
  • Tran D et al. (2003) "Inflammatory macrophage nuclear factor-kb and proteasome activity are inhibited following exposure to inhaled isobutyl nitrite." Journal of Leukocyte Biology. Vol 69,April 2001:639-644.
  • Casper et al. (2002) "Correlates of prevalent and incident KS-associated herpesvirus infection in men who have sex with men." Journal of Infectious Diseases 2002 April 1; 185(7):990-993.Epub 2002Mar. 11. PMID 11920325.
"These results demonstrate that in vivo exposure to an inhalant nitrite results in altered tissue expression of vascular endothelial growth factor (VEGF) and its receptors, suggesting that some of its toxicological effects may be mediated partly through a mechanism involving angiogenesis." PMID 14521929.
  • Ponnappan U, Soderberg LS. (2001). Inflammatory macrophage nuclear factor-kappaB and proteasome activity are inhibited following exposure to inhaled isobutyl nitrite.. PMID 11310851
"A series of 14 daily, 45-min exposures of mice to 900-ppm isobutyl nitrite in an inhalation chamber reduced the number of peritoneal exudate macrophages (PEM) by 35% and the number of resident peritoneal macrophages (RPM) by 18%. Although the tumoricidal activity of RPM was not affected by the inhalant, the cytotoxicity of PEM was reduced by 26%. The induction of nitric oxide (NO) and the inducible NO synthase (iNOS) protein in PEM were inhibited by the inhalant to a similar extent. Inhibition of NF-kappaB activation in PEM from mice exposed to the inhalant corresponded to reduced degradation of the NF-kappaB inhibitor, IkappaB alpha. Proteasome-associated, enzymatic activity was compromised in PEM from inhalant-exposed mice, suggesting that inhaled isobutyl nitrite compromised macrophage, tumoricidal activity by inhibiting proteasomal degradation of the NF-kappaB inhibitor, IkappaB alpha."
  • Pauk et al.(2000). "Mucosal shedding of human herpesvirus 8 in men." New England Journal of Medicine; 2000 Nov 9;343(19):1369-77. PMID 11070101.
  • Kielbasa W. et al.,(2000)." Nitrite inhalation in rats elevates tissue NOS III expression and alters tyronsine nitration and phosphorylation." Biochemical and Biophysical Research Communications; 2000 (275): 335-342. PMID 10964667.
  • Guo G et al. (2000). "Acute exposure to the abused inhalant, isobutyl nitrite, reduced t cell responsiveness and spleen cellularity." Toxicology Letters 116:151-158. PMID 10906432.
  • James JS. (1999). Poppers: large cancer increase and immune suppression in animal tests, AIDS Treat News 317. PMID 11366993
"A study on mice injected with cancer cells and then exposed to isobutyl nitrite (poppers) revealed that inhalant-treated mice developed tumors more readily and rapidly than control mice. The control mice were also injected with cancer cells, but only breathed air. Related studies found that poppers suppress certain immune functions involved in killing tumor cells. These studies suggest that further research of persons with HIV/AIDS who use poppers is needed to determine if they are at a high risk for developing malignancies."
  • Soderberg LS. (1999). Increased tumor growth in mice exposed to inhaled isobutyl nitrite., Toxicol Lett. PMID 10048747
"To determine if exposure to nitrite inhalants could alter tumor growth, syngeneic PYB6 tumor cells were injected into groups of mice. Exposure of these mice to inhaled isobutyl nitrite increased both the tumor incidence and the tumor growth rate by almost 4-fold. Following only five daily exposures to the inhalant, the induction of specific T cell mediated cytotoxicity was inhibited by 36%. Similar inhalation exposures inhibited the tumoricidal activity of activated macrophages by 86%. The data suggest that exposure to abuser levels of a nitrite inhalant compromised tumor surveillance mechanisms."
  • Soderberg LS. (1998). Immunomodulation by nitrite inhalants may predispose abusers to AIDS and Kaposi's sarcoma., J Neuroimmunol. PMID 9610684
"Inhalation exposure to the nitrites produce a nonspecific cytotoxicity, depleting many cells of the immune system. Apparently distinct from this cytotoxicity, inhalation of the nitrites impairs a variety of immune mechanisms, affecting both humoral and cell-mediated immunity. [...] Thus, nitrite inhalants may impair immune resistance to infection and actively promote viral replication and tumor growth."
  • The poppers-HIV connection. (1999). Focus. PMID 11366670
"In addition, research has found that popper use suppresses natural killer (NK) cell function, which increases vulnerability to infectious agents, produces sustained alterations in the immune system, and may be a Kaposi's sarcoma (KS) cofactor. The combined data implicate that the use of poppers may well pose as a significant risk factor for seroconversion."
  • James JS (1999). Poppers: more evidence of suppressed immunity., AIDS Treat News, 325. PMID 11366577.
"Evidence from studies in mice shows that exposure to isobutyl nitrite suppresses the immune system. This immune suppression allows for bacterial growth in the lungs and livers of infected mice and can inhibit the ability of mediastinal lymph nodes to respond to antigen-specific stimulation. The mechanism for immune suppression may be a reduction in CD4+ and CD8+ T cell populations in the mediastinal lymph nodes following pulmonary infection with Listeria monocytogenes."
  • Soderberg LS et al.,(1996)."Elevated TNF-and inducible nitric oxide production by alveolar macrophages after exposure to a nitrite inhalant." Journal of Leukocyte Biology; 1996;60:459-464. PMID 8864129.
  • Soderberg LS et al.,(1996)."Leukopenia and altered hematopoietic activity in mice exposed to the abused inhalant,isobutyl nitrite." Experimental Hematology; 1996,June; 24(7):848-853. PMID 8647236.
  • Soderberg LS et al.,(1996)."Acute inhalation exposure to isobutyl nitrite causes non specific blood cell destruction." Experimental Hematology;1996, April(5):592-596.PMID 8605963.
  • Soderberg LS. et al.,(1996). "Inhaled isobutyl nitrite produced lung inflammation with increased macrophage TNF- and nitric oxide production." Adv Exp Med Biol;1996; 402:187-189. PMID 8787659.
  • Haverkos and Drotman (1995)."Measuring nitrite exposure in gay men: implications for elucidating the etiology of AIDS-related Kaposi's sarcoma." Genetica, 1995;95(1-3)157-64.PMID 7744258.
  • Ostrow,David G. et al.,(1995). "A Case Control study of HIV virus type 1 seroconversion and risk related behaviors in the Chicago MACS/CCS Cohort, 1984-1992.MACS. Coping and Change Study." American Journal of Epidemiology, Oct 15, 1995; 142(8)875-883. PMID 7572964.
  • Soderberg LS (1994). "T cell functions are impaired by inhaled isobutyl nitrite through a t-independent mechanism." Toxicology Letters; 1994, 70:319-329. PMID 8284799.
  • Soderberg LS (1991). "Exposure to inhaled isobutyl nitrite reduces t cell blastogenesis and antibody responsiveness." Fundamental and Applied Toxicology; 1991; 17:821-824. PMID 1778367.
  • Dax,Elizabeth et al.,(1991). "Amyl Nitrite Alters Human In Vitro Immune Function," Immunopharmacology and Immunotoxicity Vpl. 13(4):557-587. PMID 1685501."The changes in lymphocyte function observed in this study suggest that volatile nitrite inhalation results in a cycle of modest immunosuppression followed by gradual recovery after cessation of drug inhalation. NK(natural killer)activity was most noticeably effected and was the slowest to recover."
  • Soderberg LS et al., (1991)."Exposure to abused inhalant, isobutyl nitrite, compromise both antibody and cell-mediated immunity." Adv Exp Med Biol., 1991; 228: 265-8. PMID 1835258.
  • Dunkel, V. et al.(1989) "Mutagenicity of Some Alkyl Nitrites Used As Recreational Drugs." Environmental and Molecular Mutagenesis. 14:115-122.: "To evaluate further the genotoxic activity of these chemical, six nitrites, including those commonly used by homosexuals for sexual gratification, were selected for testing in the mouse lymphoma TK+/-and Salmonella typhimurium mutagenicity assays. One chemical, n-amyl nitritem, was negative in the mouse lymphoma assay, while other five chemicals,n-butyl, isobutyl, iso-amyl, sec-butyl, and n-propyl nitrite were positive. All six compounds were positive for the Salmonella assay." PMID 2569972.
  • Harry W. Haverkos, M.D., John A. Dougherty, Ph.D. (1988). Health Hazards of Nitrite Inhalants, NIDA Research Monograph 83
  • Sidney Mirvish et al., "Mutagenicity of Iso-Butyl Nitrite Vapor in Ames Test and Some Relevant Chemical Properties, Including the Reaction of Iso-Butyl Nitrite with Phosphate", Environmental and Molecular Mutagenesis, 1993;21:247-252.
  • Khaled M. et al. (1986)"Inactivation of B-12 and Folate Coenzymes by Butyl Nitrite as Observed by NMR: Implications on One-Carbon Transfer Mechanism." Biochemical and Biophysical Research Communications. Vol.135 No.1:201-207.: "The significance of this experiment is the loss of the one-carbon fragment, namely the 5N-methyl group, with the subsequent destruction of the coenzyme. Frequent butyl nitrite inhalation entails therefore the risk of B12 and/or folate deficiency with consequent impairment of the immune function." PMID 3954771.
  • Lauritsen, John and Hank Wilson. (1986) Death Rush: Poppers and AIDS, Pagan Press. Contains an extensive bibliography on nitrite inhalants and possible relationships to Kaposi's sarcoma and AIDS. This book is currently out of print, but may be downloaded in zip format as part of the appendix to the following paper: [10].
  • Newell GR, Adams SC, Mansell PW, Hersh EM (1984). Toxicity, immunosuppressive effects and carcinogenic potential of volatile nitrites: possible relationship to Kaposi's sarcoma., Pharmacotherapy. PMID 6150466
"These products have been found to be profoundly immunosuppressive for human lymphocytes in vitro, and their by-products when metabolized into N-nitroso compounds have been known to be highly carcinogenic in many animal species."
  • Lotzova, Eva et al.,(1984). "Depression of murine natural killer cell cytotoxicity by isobutyl nitrite." Cancer Immunology and Immunotherapy; 1984;17:130-34. PMID 6235910.
  • Hersh E.M., Reuben J.M., Bogerd H., Rosenblum M., Bielski M., Mansell P.W.A., Rios A., Newell G.R., Sonnenfeld G. (1983), Effect of the recreational agent isobutyl nitrite on human peripheral blood leukocyte and on in vitro interferon production. Cancer Res 43, 1365
  • Jorgensen K.A., Lawesson S.O. (1982), Amyl nitrite and Kaposi's sarcoma in homosexual men. N. Engl. J. Med. 307, 893
  • Mirvish S.S., Ramm M.D., Bobcock D.M. (1988), Indications from animal and chemical experiments of a carcinogenic role for isobutyl nitrite. In: Health Hazards of Nitrite Inhalants (Haverkos H.W. Dougherty J.A., eds.) NIDA Res Monogr 83, National Institute on Drug Abuse, Washington DC, P 39
  • Newell G.R., Mansell P.W., Spitz M.R., Reuben J.M., Hersh E.M. Volatile Nitrites Use and Adverse Effects Related to the Current Epidemic of the Acquired Immune Deficiency Syndrome. Am. J. Med. 78:811,1985.
  • Harry Haverkos et al., "Disease manifestation among homosexual men with acquired immunodeficiency syndrome: A possible role of nitrites in Kaposi's sarcoma, Sexually Transmitted Diseases, October-December 1985. Harry Haverkos and John Dougherty, editors; Health Hazards of Nitrite Inhalants, NIDA Research Monograph 83, 1988
  • I. Quinto, "The Mutagenicity of Alkylnitrites in the Salmonella Test" (translation from the Italian), Bolletino Societa Italiana Biologia Sperimentale, 56:816-820, 1980.
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