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POPPERS or Alkyl Nitrites
Wikipedia contributors, "Poppers," Wikipedia, The Free Encyclopedia (accessed October 30, 2006).
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'Poppers' is the slang name for a group of drugs that are usually found in liquid form and typically inhaled through the nose. Scientifically know as [[alkyl nitrites]] ([[organic compound]]s with the basic formula R-O-N=O, where R is any organic group), [[amyl nitrite]] (historically used for the treatment of [[angina]], among other legitimate medicinal uses), [[butyl nitrite]], [[isobutyl nitrite]], [[isopropyl nitrite]], [[ethyl nitrite]], [[methyl nitrite]] as well as the disputed [[cyclohexyl nitrite]], these products have been widely used for 40 years as the primary ingredients in room deodorizer products and as [[recreational drug|recreational drugs]]. The vapours of poppers are inhaled directly from a bottle, inducing an almost-instant, euphoric head rush; the body's [[smooth muscle]]s are relaxed. As a recreational drug, they are primarily used to enhance the sexual experience, particulary among [[gay men]].
==Basics==
Cyclohexyl nitrite, butyl nitrite, isobutyl nitrite, and other light alkyl nitrites can be found as the primary ingredient in so-called 'room odorizers', 'video head cleaners', and 'leather cleaners', despite the malodorous nature of some of these compounds. Traditionally marketed in small glass bottles, they are, like amyl nitrite capsules, referred to as '''poppers'''. Nitrite-based odorizers are available in [[adult bookstore]]s 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]]. Some manufacturers include qualifying statements on their web sites such as: "''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.''" Some web site dealers provide disclaimers on their sites as well.
The alkyl nitrite which has been used medicinally, amyl 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 or allowed to permeate the room. 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 many more doses.
==Legality==
It is illegal to sell poppers as "inhalants" in the United States and many other jurisdictions. This is the case regardless of the formula. Most brick and mortar retailers circumvent this restriction by selling them as 'video head cleaner', 'room odourizer', 'leather cleaner', etc. Web dealers are less prone to be careful, because of their ability to hide their identity. Many websites selling 'poppers' are more explicit in their description of how the product can be misused as an inhalant.
There are occasional press accounts of raids in the United States, and even arrests associated with the sale of these products, resulting most often in confiscation of the dealer's stock and/or an accompanying fine.
==Usage==
Inhaling nitrites relaxes [[smooth muscles]] throughout the body, including the [[sphincter]] muscles of the [[anus]] and the [[vagina]]. This causes the blood vessels to dilate (which causes a sudden drop in blood pressure), increases heart rate, and produces a sensation of heat and excitement that can last for several minutes.
The recreational use of alkyl nitrites is typically an attempt to enhance a sexual experience. The [[head rush]], [[euphoria]], and sensations of relaxation that result from the blood pressure drop are often felt to increase [[sexual arousal]] and desire. At the same time, the relaxation of the [[sphincters]] of the [[anus]] and [[vagina]] can make penetration easier. Similarly, a temporary reduction in the stiffness of the [[erection]] can also make penetration easier or more comfortable, so long as an adequate degree of stiffness is retained. Some people find poppers can also moderate their [[gag reflex]], facilitating [[oral sex|fellatio]]. Others report that poppers can enhance and prolong orgasms.
While anecdotal evidence reveals that both men and women can find the experience of using poppers pleasurable, this experience is not universal. Some people report that the smell of second-hand poppers (which delivers a relatively small dose) can cause head-aches and nausea. Others feel the reduction in erection stiffness can interfere with sexual performance. Some men find that poppers can interfere with their ability to attain or maintain an erection. These undesirable effects occur for most people as exposure increases, reducing the likelihood of a dangerous overdose.
The use of poppers was popularized in [[Radley Metzger]]'s [[1972]] [[cult classic]] film ''[[Score (film)|Score]]''. In the film, a [[bisexuality|bisexual]] woman glides them under the nose of a [[heterosexuality|heterosexual]] woman in an attempt to loosen her [[vagina]] for seduction. During the 1970's and 1980's, the mainstream media often wrote about poppers with stories similar to this front page [http://alkylnitrites.blogspot.com/2006/04/1977-front-page-story-on-alkyl.html ''Wall Street Journal'' article]. They were discussed again in the mainstream news at the turn of the century when the danger of combining nitrites with [[sildenafil]] ([[Viagra]]) or other impotence drugs became known. (e.g. [http://psa-rising.com/medicalpike/vaigracardiodeaths031500.htm ''Viagra May Cause Heart Attack Deaths In Younger Men With No Heart Problems, Study Finds'']), and again on the anniversary of the first quarter century of the AIDS epidemic, in a feature article in the June 5, 2006 edition of New York magazine ([http://nymetro.com/news/features/17158/ AIDS in New York: A Biography]).
Alkyl nitrites are often assumed to be used exclusively or primarily by [[homosexuality|homosexual]] men, but usage is reportedly popular among [[heterosexuality|heterosexual]] men and women as well.[http://alkylnitrites.blogspot.com/2006/04/1977-front-page-story-on-alkyl.html] This can be compared with the propaganda directed at [[Ecstasy (drug)|Ecstasy]] in an attempt to discourage use by the majority.
Nitrite users tend to be adults rather than adolescents.
Some nitrite users combine them with other recreational drugs to enhance the effects. For example, combining ecstasy with poppers reportedly produces an intense rush of euphoria and physical pleasure. Since the rise of [[Disco]] in the mid-[[1970s]] and of [[Acid House]] music in the late [[1980s]], nitrite inhalants have been a large part of the ''disco scene'' and [[rave|rave culture]], used on the dance floor to heighten the experience of music and lights.
==Chemistry==
Alkyl nitrites can be synthesized from [[primary alcohol]]s according to the following [[RXN|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==
{{not verified}}
The assumption by some that the light alkyl nitrites posed a significant health hazard was the subject of contentious debate beginning in the mid-1970’s.
Throughout the 1980's and 90's, the focus of such debate was on a possible link between nitrites and [[AIDS]], or AIDS-related illnesses such as [[Kaposi's sarcoma]].
After a 1983 meeting between the [[Centers for Disease Control|Centers for Disease Control's]] principal AIDS investigator, James Curran, and Joseph Miller, the president of Great Lakes Products, Inc. (a then-major manufacturer of popular nitrite brands such as Rush, who sought the meeting with Dr. Curran in order to discuss a possible poppers-AIDS connection -- before [[HIV]] was discovered), Miller reported in a press release that poppers had been exonerated by the Center for Disease Control. Dr. Curran later pointed out in a September 27, 1983 letter to Miller that he had been misinterpreted in the press release. Curran stated that: “Other health hazards 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.”
Two years later, in 1985, after a demand from Hank Wilson, creator of the 'Committee to Monitor Poppers', that Dr. Curran take an anti-poppers stand, Dr. Curran responded to the one-man committee by telling Wilson that "Current data does not warrant an anti-poppers campaign". -- May 6,1985 letter to the Committee to Monitor Poppers
Upon the discovery of HIV and the definitive research that showed HIV to be the cause of AIDS, poppers were dismissed as the cause of AIDS. However,the possible role of popper use as a risk factor in HIV infection continued to be explored. It is thought by some that even the insignificant immunosuppressive effect of poppers, may increase susceptibility to HIV infection and also HHV-8 infection, or that they may affect sexual behavior increasing risk for infection, though, after numerous studies over the past twenty years, there is little data to support either of these theories.
It has also been speculated by some that because Kaposi's sarcoma occurred in homosexual AIDS-patients 20 times more often than in non-homosexual AIDS-patients, some cofactor must be involved beyond the virus HIV itself. Poppers were suggested as a candidate for that cofactor, though studies have been contradictory and have not supported such theories.
Nitrites do present possible health hazards, however, which can include: high doses of Nitrites may cause [[methemoglobinemia]], particularly in individuals predisposed towards such a condition.[http://www.medsafe.govt.nz/Profs/datasheet/a/Amylnitrateinh.htm]. However, as the authors point out, it would take 'excessively high doses of poppers, administered chronically, to possibly cause methemogtlobinaemia (and that methemogtlobinaemia is readily reversible with the administration of methylene blue). It is speculated that use with [[Viagra]] can cause heart failure (though there is no indication in the literature that such heart failure has ever occurred), and individuals with [[anaemia]] or heart, breathing or blood pressure conditions may be at risk of complications{{Citation needed}}. It’s also suggested that since pressure in the eye and cranium is increased, individuals suffering from [[glaucoma]] or traumatic head injuries may have an added risk of negative short or long term effects{{Citation needed}}.
Impure alkyl nitrites can burn the skin on contact. All alkyl nitrites can be fatal if swallowed or injected. It has also been reported by some users of an association with mild to extreme headaches.
There has also been significant input from researchers and governmental officials in the USA and other countries, that poppers do not pose a significant hazard to users [http://alkylnitrites.blogspot.com/2006/04/this-is-list-of-statements-about.html]. Some experts, including Thomas P Lowry, MD, went even further. In a research paper published in the [http://alkylnitrites.blogspot.com/2006/04/inhalable-nitrites-may-be-nearest.html Journal of Psychoactive Drugs; Jan-Jun, 1982; Vol. 14(2): 77-79], Dr. Lowry not only addressed the issue of potential hazards of poppers, but also discussed their use as aphrodisiacs, thereby combining a discussion of effects and sociological aspects.
Over the past quarter century, prominent AIDS researchers and activists, such as [http://alkylnitrites.blogspot.com/2006/04/controversy-over-poppers.html Paul Varnell] and [http://alkylnitrites.blogspot.com/2006/04/are-poppers-safe.html Bruce Voeller] (the scientist who gave AIDS its name) made their concerns known about what they believed to be misrepresentations about poppers.
==Medical uses==
Alkyl nitrites are clinically utilized as a vasodilator in order to treat angina, and as part of the treatment regimen for [[cyanide]] poisoning. Most [[Certified first responder]]s and [[Emergency department]]s in the United States maintain a supply of Amyl Nitrite for such use.
==Street names==
Common street names for these products include:
* Rush
* Poppers
* Snappers
* Brown Bottle
==External links==
*[http://www.torontovibe.com/drug_information.html#pop1 Toronto Canada Harm Reduction], information on poppers from a [[harm reduction]] perspective
*[http://dancesafe.org/documents/druginfo/poppers.php Poppers at DanceSafe UK], poison control and harm reduction information
*[http://nepenthes.lycaeum.org/Drugs/Misc/volnitr.html Psychosexual Aspects of the Volatile Nitrites], by Thomas Lowry, MD
*[http://www.gay.com/health/sexuality/article.html?sernum=770 Sex Talk], a [[homosexual]] social perspective on poppers
*[http://poppersmyth.typepad.com/aids_and_poppers/ The Art of Scientific Scrutiny: Investigating the Poppers-AIDS Hypothesis], by Christine Weber
*[http://www.erowid.org/chemicals/inhalants/inhalants_info5.shtml Confusion Between Nitrites & Nitrates], at [[Erowid]]
==References==
{{POV-Section}}
*Tran DC et al.,"Effects of repeated in vivo inhalant nitrite exposure on genes expression in mouse liver and lungs." Nitric Oxide 2006 Jun;14(4):279-289. "In conclusion, multiple exposure to inhalant nitrite appeared to cause alterations in the expression of a number of genes relating to cancer and angiogenesis,.."
*Mbullaiteye Sam et al.,"Risk factors for human herpesvirus 8 seropositivity in the AIDS Cancer Cohort Study." Journal of Clinical Virology Volume 35, Issue 4, April 2006, Pages 442-449.
*Chin-Hong PV et al.,"Age-related prevalance of anal cancer precursors in homosexual men: the EXPLORE study." J Natl Cancer Inst. 2005 Jun 15;97(12):896-905.
*Casper et al.,(2006) "HIV Serodiscordant sex partners and the prevalence of HHV-8 infection among HIV negative men who have sex with men: baseline data from the EXPLORE study." Sexually Transmitted Infections 2006:Vol 82 Issue 3: 229-235.
:::'''''ANALYSIS OF STUDY:''''' It's important to note that, first of all, nitrite use is not mentioned in the abstract of the article, indicating its lack of importance in herpes virus 8 (HHV-8) infection. The focus of the article is sexual behavior related to HHV8. In fact, nitrite use is barely mentioned in this article.
:::Although the study did find an association between nitrite use and HHV-8, the authors state that nitrite use is “also significantly associated with median number of sex partners of any HIV status, having more than the median number of HIV unknown sex partners, and performing rimming with >5 lifetime HIV unknown sex partners.” This makes is impossible to distinguish which behavior is causing HHV-8 infection. The authors even say that “the question of whether the relation between amyl nitrates and HHV-8 is biological or behavioural remains unanswered“.
:::It is not logical to cite references, such as this one, that vaguely mention nitrite use as a risk factor for Kaposi’s sarcoma, as evidence of a causal connection. This appears to be an attempt to create the appearance of a body of scientific publications supporting such claims, when there is no such body of data.
:::These types of articles should not be cited with regard to nitrites.
* 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
*Soderberg et al (2004) Increased tumor growth in mice exposed to inhaled isobutyl nitrite. Toxicology Letters, 152:35.
:::'''''ANALYSIS OF STUDY:''''' The investigators chose the PYB6 tumor, a syngeneic, virus-induced sarcoma, but it does not have the unique growth characteristics of KS and they state that it “might respond differently to changes in immunocompetence”.
:::Since they are not measuring the effects of nitrite on KS, the logical choice, the results could be irrelevant.
:::They state studies of immune function using PYB6 cells as target cells in vitro were not fruitful, as the PYB6 cells were not suitable for in vitro cytotoxicity assays, so they could not determine if altered immune function affects PYB6 tumor growth (what they are claiming.)
:::They end with “it is generally acknowledged that specific CTL are important in controlling HIV replication in the early stages following infection. The nitrite-induced immunosuppression reported here was not as profound as occurs in the late stages of AIDS and was transient, recovering to normal levels within 14 days after termination of exposure”.
:::This also does not correlate with their claim that nitrite use is important in AIDS.
*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.
:::'''''ANALYSIS OF STUDY:''''' Soderberg, et al state that exposure to isobutyl nitrite reduced the induction of specific cytotoxic T-cells and macrophage tumoricidal activity, and “signaling through the macrophage NF-κB pathway was impaired following inhalant exposure. NF-κB-dependent induction of macrophage nitric oxide synthase (NOS2) and subsequent production of nitric oxide were consequently inhibited. The present study examined the effects of nitrite inhalant exposure on another macrophage product important in innate immunity, IL-1β. The production of IL-1β was inhibited at both transcriptional and post-translational level.”
:::Although this sounds impressive, it is very unlikely that one compound can have this many effects that are not a result of toxicity from excessive doses.
*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.
:::'''''ANALYSIS OF STUDY:''''' Soderberg is one of the authors on this paper, again demonstrating bias. The reasoning of this paper was very difficult to follow, but essentially it is a repeat of a previous paper with the exception that they demonstrated nitrite effects in 5 days instead of 14 days.
:::Phosphorylation of IκBα is a prerequisite for ubiquitination and proteasome-dependent degradation of IκBα, freeing NFκB to move into the cell nucleus and affect gene expression. They could not demonstrate an inhalant-associated decrease in IκBα degradation, and they stated that it is likely that inhalant exposure inhibits activity of the IκBα kinase, or it may act on an upstream component in the signaling cascade. However they did not measure these parameters to demonstrate that these are a mechanism of action.
:::The researchers state that “data suggested that inhalant exposure likely inhibited macrophage (nitric oxide) NO production by blocking NFκB-mediated activation signaling and promoting poly ubiquitination of NOS2.”
:::It is astounding that researchers can publish this much data that is conflicting and obviously does not show target selectivity of nitrites.
* Tran et al (2003) Inhalant nitrite exposure alters mouse hepatic angiogenic gene expression. Biochemical and Biophysical Research Communications, 310:439.
:::'''''ANALYSIS OF STUDY:''''' In this study, the dose for mice was 1400 ppm for four hours, which is even higher exposure than Soderberg. The utilization of this high dose negates any results that may be observed. The authors give as a rationale for performing the research that organic nitrites (NO donors) in vitro studies have shown NO to stimulate vascular endothelial growth factor (VEGF) protein and mRNA expression. VEGF is essential for tumor growth and metastasis.
:::In the discussion of this paper, another Soderberg article is referenced presenting the fact that NO is liberated by nitrite, but exogenous NO does not produce the immunotoxicity observed following exposure to isobutyl nitrite. This does not make sense because NO mediates macrophage tumoricidal activity; as a result, NO liberation would be beneficial.
:::Other conflicting data presented included that inhalant nitrite exposure also significantly suppressed the gene expression of Smad5 and Smad7 in mouse liver. Smads regulate transforming growth factor-β-dependent (TGF-β) gene expression, which controls cell proliferation, differentiation, apoptosis, migration, and extracellular matrix production. Smad5 plays an important role in angiogenesis and Smad7 is important in negative feedback regulation of TGF-β.
:::Since these Smads have opposite effects on cancer proliferation, one would not expect both to be suppressed if nitrite had carcinogenic effects.
:::Another area of concern is that these authors do not address why there were no changes in lung VEGF expression, the increase was seen in the liver. “This observation is somewhat counter-intuitive, since the nitrite exposure concentration is expected to be higher in the lung than in the liver.“
:::This statement indicates that the authors are unclear about the meaning of their results.
*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.
:::'''''ANALYSIS OF STUDY:''''' This article begins with statements about how difficult it is to establish a causal relationship between behavior and infection with KSHV (Kaposi’s sarcoma-associated herpesvirus): “However, findings in these investigations regarding specific sexual behaviors that may transmit KSHV are conflicting and have led to the lack of a consensus about modes of acquisition…Failure to definitely identify behaviors that may predispose to infection with KSHV is due to many factors… ”. These types of remarks delineate the complexity of linking any type of behavior with sexually transmitted diseases. Researchers cannot conclude or agree on what type of sexual behavior predisposes for KSHV or HIV, much less drug use (nitrites in particular).
:::In this study, Casper lists nitrite use as a behavioral correlate of prevalent KSHV infection. This does not establish a causal relationship between the two. Actually, the odds ratio (OR) for nitrite use in KSHV seropositive was given as different values, depending on how they analyzed the data, which further confounds the issue.
:::Also, they state that “Amyl nitrate use has been reported elsewhere, although not as a risk for incident KSHV infection...A biologically plausible model for amyl nitrite use and acquisition of KSHV remains unclear...”
:::The results of this paper are not conclusive and the final sentence of the publication sums up the inability of research to date to determine that exact role of nitrite use in KSHV infection, if any: “Current uncertainty limits our ability to provide a clear and effective public health message to high-risk populations about methods to reduce KSHV transmission and acquisition.”
* Ponnappan U, Soderberg LS. ('''2001'''). ''Inflammatory macrophage nuclear factor-kappaB and proteasome activity are inhibited following exposure to inhaled isobutyl nitrite.''.Journal of Leukocyte Biology, Vol. 60,April 2001: 639-644. 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."
:::'''''ANALYSIS OF STUDY:''''' Although the authors demonstrate a reduction of nuclear NFκB in activated macrophages (an immune response), nitrite exposure also reduces un-activated macrophage NFκB, which could be an indication of toxicity.
:::A clear demonstration of nitrite’s reduction in immune response would have been shown had the nitrites had no affect on un-activated macrophages.
:::The discussion of this paper is very confusing, as the authors attempt to make sense of their own contradictory data. They report that although isobutyl nitrite was shown to liberate NO, inhaled NO at a concentration equivalent to that produced by 900 ppm isobutyl nitrite did not alter resident macrophage tumoricidal activity.
:::NO liberation would not affect macrophage tumoricidal activity, because NO liberation is macrophage’s mechanism of action. They also claim that isobutyl nitrite inhibits macrophage inducible NO, which could be a feedback mechanism because nitrites liberate NO.
:::They also demonstrate that inhalant exposure inhibits macrophage NFκB activation, which is important in HIV replication. This is another contradiction.
:::Actually, the final sentence of the paper states “conflicting influences may be induced by inhalant exposure.” The authors admit the contradictions in their own paper.
*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. "Increased NOSIII expression in the liver and kidney may promote peroxynitrite formation and contribute to the increase in NT and PT immunoreactivity. ISBN inhalation may thus cause changes in cellular signaling involving tyrosine phosphorylation. These findings may suggest a mechanistic basis for the apparent immunotoxicity associated with nitrite abuse."
:::'''''ANALYSIS OF STUDY:''''' In these experiments, rats were exposed to 109 and 1517 ppm isobutyl nitrite for four hours, which is excessive and does not represent human exposure.
:::The authors did not find alterations in NOS expression in the lungs or spleen, which according to Soderberg’s hypothesis, they should have found.
:::They reported an increase in the kidney and liver, which are organs of detoxification, and it is unclear what an increase in NOS expression in these organs means. They do not address why there is differential expression.
:::Also it is not understood why they do not measure macrophage NOS expression, which is the proposed tumoricidal mechanism of macrophages. If nitrites diminish NOS in macrophages, it would support a role for nitrites in depressing tumoricidal activity.
*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.
:::'''''ANALYSIS OF STUDY:''''' This work was performed in Soderberg’s lab, making it yet another reference by himself.
:::Guo states there is no change in body or spleen weight, yet spleen cells are decreased.
:::In another paper, Soderberg reported no change in spleen cell cellularity, yet in this publication it is decreased.
:::Although there was a decrease in spleen cells, there was no reduction in CD4 and CD8 helper cells, or in differential lymphocytes. This would indicate that nitrites are not selectively reducing immune function.
:::Although a single 45 min exposure to the inhalant inhibited T cell proliferative responsiveness, it was not sufficient to overtly impair major immune mechanisms.
:::The authors also report that only after the 14-day exposure were they able to see a decrease in T-dependent antibody responses.
:::These results are not definitive.
* 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."
:::'''''ANALYSIS OF STUDY:''''' All of this researcher's studies using mice suffer from a very a serious flaw; namely, that the mice are exposed to extremely large doses of nitrites when their body size is taken into account.
:::Earlier work by Soderberg (J. of Immunopharmacology, 15(7):821) reported the effects of nitrite inhalation on antibody induction of mice that were tested. They saw no changes in antibody responsiveness after administering a dose of 300 ppm isobutyl nitrite for 45 minutes a day over a 14-day period.
:::Soderberg only saw decreases in antibody production at 750 and 900 ppm isobutyl nitrite. Even at these excessively high doses, there was full recovery within seven days, once again demonstrating reversibility of nitrite effects on immune function, despite the high doses.
:::Since Soderberg's group did not observe their desired effects at a dose which might not be toxic to the animals, this probably explains why they chose this dosing paradigm for their future work.
:::Although Soderberg reported an increase in incidence and size of tumors, the dose was too high to make any claims. Furthermore, the exposures did not significantly affect body weight, spleen weight, or spleen cellularity, which was reported in other articles. There are many contradictory research results published on a variety of different parameters, making it difficult to ascertain the actual effects of nitrites.
*Woody, et al (1999) Non-injection substance use correlates with risky sex among men having sex with men: data from HIVNET. Drug and Alcohol Dependence 53:197.
:::'''''ANALYSIS OF STUDY:''''' Hank Wilson includes this reference in the various versions of his bibliography of references which he claims prove poppers to be hazardous.
:::Associations between substance use and sexual behavior were examined among 3220 seronegative men. The odds ratio (OR) was low for nitrite inhalants (some use-OR= 1.6, heavy use-OR= 2.18).
:::This is in dramatic contrast to other studies, some of which give OR’s as high as 33. The large range of OR’s indicates a lack of consistency between results.
:::Although there appears to be a relationship between alcohol or drug use and an increased sexual risk among MSM, it is clear that these relationships are complex and difficult to evaluate. Disparate findings can be explained in many ways including inability to evaluate substance use patterns in the context of the sexual encounter, comparing populations with different ages or cultural features, and limitations in power resulting form small sample sizes which make it impossible to evaluate possible confounds such as demographic contributions of different substances of levels of use.
:::Here the respondents state nitrite use is 29%, compared to marijuana use 49% and alcohol use 89%. Interestingly, nitrite use is the lowest percentage, suggesting that it is less related to risky sex than other substances.
* ''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."
:::'''''ANALYSIS OF STUDY'':''' This reference should not even be included here. Surprisingly, it's link takes you to a web page on "PubMed", which has no other information. We are not told who the author is, nor is there a way to even access this so-called study.
:::This reference makes vague and unsubstantiated claims but gives no support or any proof for any of them. It uses wiggle-room phrases like "May be....a cofactor", and "...may well pose a significant risk.....".
:::It is indisputably inappropriate to try to give the appearance of a larger body of work by using this kind of unsubstantiated fluff to boost a reference list. This is a form of cheating, and lessens the integrity of every other item posted by this person in this reference list.
* 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."
*Chesney, et al (1998) Histories of substance use and risk behavior: Precursors to HIV seroconversion of homosexual men. Amer J Public Health, 88:113.
:::'''''ANALYSIS OF STUDY:''''' Hank Wilson includes this reference in the various versions of his bibliography of references which he claims prove poppers to be hazardous.
:::This is a report generated from data from surveying the San Francisco Men's Health Study cohort.
:::Although they do not discuss the implications of this, history of consistent use of amyl nitrite or amphetamines strongly affected seroconversion, while current use of these drugs did not. The data does not support a role for nitrite use in seroconversion.
:::Chesney did not measure whether substance use occurred at the time of sexual activity that may have caused seroconversion. This is an important factor.
* 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."
:::'''''ANALYSIS OF STUDY:''''' This is a review article.
:::In the conclusions Soderberg mentions that chronically impaired immunity could reduce resistance to HIV infections, but his own research shows the nitrite immune suppression is reversible.
:::Soderberg states that the LD 50 for mice is 1033 ppm for one hour, which means that at this dose, half of the mice will die, so giving 900 ppm for 45 minutes is approaching the lethal dose.
:::Furthermore, other researchers cited are also using near lethal doses. This supports my claim that critical differences in body weight between humans and mice were not considered.
:::Another discrepancy is that Soderberg references work by others that does not show a change in human CD4 and CD8 ratios after nitrite exposure, which occurs in AIDS or immonocompromised individuals.
:::Although in one of his publications he shows a decrease in mouse natural killer (NK) cell activity and proposes it as a nitrite mechanism for immunotoxicity, he states that two other laboratories (including his) were unable to substantiate this alteration.
Ruiz, et al (1998) Risk factors for human immunodeficiency virus infection and unprotected anal intercourse among young men who have sex (YMSM) with men. Sexually transmitted diseases, 25: 100.
:::'''''ANALYSIS OF STUDY:''''' Hank Wilson includes this reference in the various versions of his bibliography of references which he claims prove poppers to be hazardous.
:::In this study, Ruiz relied on self reporting, the reliance of which from YMSM is unknown. He also did not distinguish between frequency of use, thus the analysis treated those having used a drug once the same as those who used that drug daily. He also grouped nitrite use with another stimulant, crack, which further confounds his results.
:::Although Ruiz found a slight positive association between recent use and recent UAI, the association between lifetime use and HIV infection is much larger.
:::The first result would indicate no relationship between UAI and nitrite use and the second result is unexplained.
*McFarland, et al. (1997) Estimation of human immunodeficiency virus (HIV) seroincidence among repeat anonymous testers in San Francisco. American Journal of Epidemiology, 146:662.
:::'''''ANALYSIS OF STUDY:''''' Hank Wilson includes this reference in the various versions of his bibliography of references which he claims prove poppers to be hazardous.
:::In this study, the investigators claimed that nitrite use was significantly associated with seroconversion. However, only 42 out of 789 men who reported nitrite inhalation during sex in the last year were HIV-positive.
:::Since the incidence of seropositivity in nitrite users is so small, one cannot establish a statistical significance using this data.
*Soderberg and Flick (1997) Acute blood toxicity of the abused inhalant, cyclohexyl nitrite. Int J Immunopharmac, 19:305.
:::'''''ANALYSIS OF STUDY:''''' In this report cyclohexyl nitrite produced anemia and leucopenia. Two important issues must be noted: there were no dose related effects noted, and there was a nonspecific cell reduction.
:::A dose response relationship is essential in pharmacology to establish an effect. Generally when this is not the case, toxicity is evident. The nonspecific cell reduction also is an indication of toxicity.
:::Cyclohexyl nitrite did not decrease macrophage tumoricidal activity, which contradicts a previously published report.
:::Soderberg states in another paper that there are differential effects of cyclohexyl and isobutyl nitrite, yet he is obtaining different results with the same compound.
*Robins, et al. (1997) Do homosexual and bisexual men who place others at potential risk for HIV have unique psychosocial profiles? AIDS Education and Prevention 9(3):239.
:::'''''ANALYSIS OF STUDY:''''' This article has very little data (two tables). Although they claim that HIV-positive (n=369) homosexual and bisexual men exhibit more frequent nitrite use than HIV-negative (n=156) men, there is not a significant difference between the two groups.
:::Men engaging in risky sexual practices reported more popper use than men practicing safer sex, although his effect was not significant. They also tended to use more alcohol than the safer sex group.
:::This study reported that for the variables they studied (demographics, social support, psychological status, coping, substance use) the correlates of risky behaviors were the same in HIV positive and negative men. The study's cross-sectional design does not allow one to draw causal inferences and therefor does not support Hank Wilson's hypothesis.
*Kalichman (1997) Continued high-risk sex among HIV seropositive gay and bisexual men seeking HIV prevention services. Health Psychology, 16(4):369.
:::'''''ANALYSIS OF STUDY:''''' In this article, only 19% of the HIV-positive men surveyed used nitrite inhalants, with the average frequency of use over a three month period being 1.9 times.
:::Furthermore, of the men who engaged in unprotected anal sex, the average frequency of nitrite use over a three month period was only 3.3 times, compared to a mean frequency of use of 0.6 times for those who did not have unsafe sex. Although the author used statistics to show a significant difference between those who did and did not have unprotected anal sex, the raw data indicates an extremely low use of nitrites among any of the men. It is highly unlikely that using a drug 3.3 times over a three month period can cause unsafe sex.
:::This is a good example of how statistics can be used to mislead the reader.
:::As a final note, the nationwide prohibition on sales of volatile nitrites in the United States in 1991 has not had an appreciable effect on either the use of inhalant nitrites by men in the Chicago MACS/C. Since nitrites are readily available by mail order and in pornographic bookstores and movie theaters, it appears that legal prohibition does not change abuse behaviors. In fact, use of these "street drugs" could be more dangerous because they may have harmful impurities.
:::This drug is probably one of the safer drugs of abuse that are available, particularly because the effects are transient. In addition, this drug is inexpensive compared to other drugs of abuse, and use of nitrites rather than the more expensive drugs may actually decrease crime and prostitution, which are commonly used by drug abusers to obtain drugs. A lower incidence of prostitution may lead to lower levels of unsafe sex in these groups, which may be a better preventative of HIV infection than other intervention methods.
*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.
:::'''''ANALYSIS OF STUDY:''''' The reference that Soderberg gave establishing human exposure as 7000 ppm (Soderberg, et al, Experimental Hematology, 24, 846-853, 1996) does not reflect human doses.
:::In this article, which he used as a reference, Soderberg claims that abuser doses exceed 1500 ppm, which is much lower than 7000 ppm. In yet another publication by Soderberg (Fundamental and Applied Toxicology, 17:821, 1991), he stated that the actual dose levels of nitrite abusers are unknown.
:::From these disparate statements, it appears that Soderberg has no concrete data to establish the amount of an abuser dose. None the less, he arbitrarily sets the treatment dose for mice at 900 ppm for 45 minutes over a 14 day period.
:::This paper included a dose-response curve showing that a single exposure of this amount to mice caused lung hemorrhage, and prolonged treatment caused emphysema-like changes. Doses as low as 300 ppm also caused lung hemorrhage in mice. Furthermore, Soderberg did not account for the difference in lung size between humans and mice.
:::This is a very serious error, and because of this, he is probably utilizing a treatment dose that is toxic to mice. Perhaps Soderberg did not get his anticipated results when exposing animals to lower doses, and it turns out that nitrites are not harmful at more physiological doses. Surprisingly, this group continued to publish studies using a dose that is clearly excessive.
:::Another major problem with this article is that it reported opposite results from Soderberg's previous studies.
:::For example, this article showed an increase in tumoricidal activity of mice lung macrophages, whereas there was a decrease in tumoricidal activity in humans in another paper by Soderberg.
:::If different results are obtained between humans and animals, this would imply that there is a difference between the two species and invalidates the use of animals in experiments.
:::Other work presented in the study showed an increase in TNF-a production of lung macrophages in response to interferon. Activated macrophages release TNF-a, which would indicate an increase in tumoricidal activity. Since macrophages kill both virally infected and cancerous cells, it follows that an increase in macrophage function would be a preventive of HIV infection and KS.
:::In regards to the data showing an increase in tumoricidal activity, Soderberg stated that this result is unexpected and may be a caused by increased lung inflammation in response to tissue damage. This is further evidence that the researcher is using an excessive nitrite dose.
:::Also, when the same investigator publishes opposite results, it is impossible to establish the true effects of nitrite use.
*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.
:::'''''ANALYSIS OF STUDY:''''' In this paper, after five mice were treated with 900 ppm isobutyl nitrite for 14 days, they exhibit a 36% decrease in white blood cell count and a 7% increase in red blood cells. The later result is unusual because nitrites have been shown to cause a decrease in red blood cells (Fundamental and Applied Toxicology, 19:169, 1992).
:::All observed blood cell changes return to baseline one week after cessation of drug, demonstrating reversibility of nitrite effect.
:::This report, and other articles by Soderberg, all suffer from the same problems; namely, their experimental design flaws include the administration of an excessive drug dose to the mice, along with the problems of low sample size, and no replication of experiments to confirm results.
:::These protocol errors, in combination with the contradictory results from different experiments by the same and other authors, make it impossible to develop firm conclusions about the effects of nitrites on the immune system.
*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.
:::'''''ANALYSIS OF STUDY:''''' This is also cited as a 1996 poster.
:::Although Soderberg reported in an earlier paper that results were seen in 5 days, he continued in this study for 14 days. Perhaps he only saw certain effects at excessive doses. An indicator of this is the nonspecific blood cell destruction, a likely result of toxicity.
:::The authors found a decrease in both red and white blood cells at 24 hours after acute exposure. It is possible that this decrease is a result of lung hemorrhage, with subsequent blood loss, induced by the high dose of nitrite.
:::Regardless, the observed changes in blood cell count were reversed within 72 hours, which again demonstrates that nitrite effects are reversible.
:::The study also described a decrease in spleen cellularity and speculated that spleen cells are mobilized to provide replacement white blood cells. If this is true, then the spleen can overcome any loss in immune function that may occur as a result of transient white blood cell loss, and serve as a compensatory mechanism to maintain homeostatic immune function.
:::Therefore, even if nitrites do cause a decrease in white blood cells, there is a rapid response to correct the imbalance.
*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.
:::'''''ANALYSIS OF STUDY:''''' This article contains the same information as a previously discussed Soderberg publication (Toxicology Letters, 104:35) with the same flaws.
:::This is an example of an investigator increasing the volume of their work by publishing duplicative results.
*Soderberg, and Barnett (1995) Inhaled exposure to isobutyl nitrite inhibits macrophage tumoricidal activity and modulates inducible nitric oxide. Journal of Leukocyte Biology, 57:135.
:::'''''ANALYSIS OF STUDY:''''' This paper is a repeat of experiments in another reference by the same author, except the tumoricidal activity of peritoneal, rather than lung macrophages, was measured.
:::Interestingly, Soderberg obtained the opposite results between the two publications. For instance, in these experiments, there was a decrease in tumoricidal activity that returns in two weeks, which contradicts their 1996 publication showing an increase in tumoricidal activity of macrophages.
:::Other data presented by Soderberg demonstrated that nitrite exposure increased TNF-a production by itself, or in combination with interferon, but caused no change in response to lipopolysaccharide or interferon and lipopolysaccharide (stimulators of TNF- a production). In contrast, the other report stated that there was no effect of nitrite treatment on TNF-a production in either the absence or presence of interferon, but an increase in TNF-a production in the presence of lipopolysaccharide or lipopolysaccharide and interferon.
:::Finally, the 1995 study reported a decrease in nitric oxide production stimulated by lipopolysaccharide and interferon, which contradicts the 1996 study. Interestingly, the author did not discuss these discrepancies.
:::When an investigator publishes results that are the opposite of each other, one cannot derive conclusions from their work.
*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 human immunodeficiency 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.
:::'''''ANALYSIS OF STUDY:''''' This study found that seroconversion correlated with marijuana, cocaine, and nitrite, but not alcohol use.
:::This contradicts other studies that found a relationship of alcohol use with HIV infection.
:::Furthermore, it was not reported if subjects used other drugs in conjunction with nitrites, which they likely did, and which would confound the issue such that nitrite use cannot be directly correlated with seroconversion.
*Ostrow, et al. (1994) Recreational drugs and sexual behavior in the Chicago MAC/CCS cohort of homosexually active men. Journal of Substance Abuse, 5(4):311.
:::'''''ANALYSIS OF STUDY:''''' This study stated that stopping nitrite use was unrelated to improvement in safer sexual behavior, which again refutes Wilson's claims.
:::In addition, they reported that nitrite use was associated with failure to use condoms during receptive anal sex among non-monogamous men only. Nitrite use was associated with the use of condoms during receptive sex among monogamous men.
:::If inhalation of nitrites was truly a causative factor in unsafe sex, it would prevail in both monogamous as well as non-monogamous relationships. More importantly, a cessation of nitrite use would lead to safer sex -- which it did not.
*Letup, et al. (1994) Seroprevalence of HIV and risk behaviors among young homosexuals and bisexual men. Journal of the American Medical Association, 272(6):449.
:::'''''ANALYSIS OF STUDY:''''' Homosexual and bisexual men recruited for this study were located in public places in San Francisco and Berkely, including street corners, dance clubs, bars, parks, and other public venues frequented by homosexuals, which is not a random sampling of homosexual and bisexual men.
:::Of the respondents who did not use nitrites during sex (n=371), 30% had unprotected anal sex, whereas of the 35 men who claimed to use nitrites during sex, 60% engage in unsafe sex. Interesting, these authors claimed that nitrite use is a predictor of unsafe anal sex. However, from this bit of data, one cannot make such a claim.
:::Finally, the author gives the disclaimer that is predominant throughout the studies presented by Wilson: "However, our data cannot distinguish whether this represents a causal association, with abuse leading to impaired judgment or disinhibition, or a marker of lifestyle among persons at high risk."
*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.
*Paul, et al. (1994) Correlates of sexual risk-taking among gay male substance abusers. Addiction, 89:971.
:::'''''ANALYSIS OF STUDY:''''' This paper reported that of the men in this study who have unprotected anal sex, 19.9% used nitrites in the past 90 days.
:::One cannot establish a role for nitrites in unsafe sex using this data. If nitrite inhalation caused unsafe sex, this percentage would be much higher.
:::At meeting of the Center for Disease Control on the connection between KS and poppers, this investigator discussed the complexities of classifying events as "risky" or "safe".There are many confounding effects among sexual behavior, drug use, and other likely health risks. He emphasized that one could never conduct a controlled study (survey) to answer the question of causality.
*Messiah (1993) Factors correlated with homosexually acquired human immunodeficiency virus infection in the era of "safer sex". Sexually Transmitted Diseases, 20:51.
:::'''''ANALYSIS OF STUDY:''''' Hank Wilson includes this reference in the various versions of his bibliography of references which he claims prove poppers to be hazardous.
:::This study also has a disparate sample size (n=201 for seronegative participants and n=45 for seropositive participants). Secondly, although inhalation of nitrites was significantly related to seropositivity, upon multivariate analysis, there was no significant difference between the two parameters.
:::Once again, after controlling for other risk factors, there is no correlation between nitrite use and seroconversion.
*Hogg, et al. (1993) Sociodemographic correlates for risk-taking behaviors among HIV seronegative homosexual men. Canadian Journal of Public Health. 84:423.
:::'''''ANALYSIS OF STUDY:''''' In this paper, the majority of the men in this study were white and part of a large urban gay community, which is a homogenous population of homosexual and bisexual men.
:::The investigators found that 55% of risk takers (n=31) used nitrite inhalants compared with 30% of the control group (n=108). It is interesting that only about half of the risk-takers use nitrites.
:::Of the non-risk-takers, a relatively large percentage used nitrites (30%), from which one could imply that the use of nitrites is also associated with safe sex.
:::In addition, they found no differences between risk and non-risk takers for cocaine, marijuana, or other drugs, which contrasts from other studies.
:::Finally, the author states that this type of behavior should not be taken to identify all people who take risks.
* 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.
:::'''''ANALYSIS OF STUDY:''''' In this study, the effects of a saturated vapor of isobutyl nitrite and a saturated aqueous solution were tested for mutagenicity using the Ames test (an indicator of cancer-causing agents).
:::The researchers demonstrated that the vapor was 11 times more mutagenic than the aqueous solution. This follows because isobutyl nitrite is not stable in an aqueous solution.
:::Isobutyl nitrite is prepared for commercial distribution in an alcohol solution. Because of this and the rapid breakdown of nitrites upon inhalation, this study is irrelevant to the question of mutagenicity of isobutyl nitrite as it is administered to humans.
:::Furthermore, there is no other data supporting the mutagenicity of this drug.
*Gaworski, et al (1992) Prechronic inhalation toxicity studies of isobutyl nitrite. Fundamental and Applied Toxicology, 19:169.
:::'''''ANALYSIS OF STUDY:''''' This article by Gaworski was cited by Soderberg as supporting his work, although it provides evidence that refutes the validity of Soderberg's model for treating mice with isobutyl nitrite.
:::In addition, Soderberg's results from experiments measuring white blood cells, are the opposite of Gaworski's.
:::Gaworksi's group investigated the toxic effects of isobutyl nitrite in short-term and chronic inhalation studies.
:::Rats and mice were exposed to doses of isobutyl nitrite ranging from 0-800 ppm. They found that 12 exposures of greater that 600 ppm, for six hours (five days a week), caused 100% mortality in rats and mice.
:::Rats exposed to 200 or 400 ppm exhibited lethargy and a hunched posture. Furthermore, these lower drug concentrations caused hyperplasia of the bronchiolar and nasal epithelia.
:::Doses of 300 ppm induced a decrease in red blood cells and an increase in white blood cells, which contradicts Soderberg's previou studies. Gaworski concluded that the highest exposure for chronic inhalation tests should not be higher than 150 ppm.
:::Although Soderberg and Gaworski were administrating similar doses, Soderberg exposed animals to nearly 10 times the amount that Gaworski recommends for long term studies over a much shorter time period. Since nitrites rapidly decompose, the lower dose over a longer time interval amounts to a final concentration that is much lower than the high dose over a short time.
:::Furthermore, considering that the dose-response curve for isobutyl nitrite is rather steep, a higher dose has a sharply increased toxicity. (Making my point about the inappropriately toxic and massive doses used.)
*Seage, et al. (1992) The relation between nitrite inhalants, unprotected receptive anal intercourse, and the risk of human immunodeficiency virus infection. American Journal of Epidemiology, 135:1.
:::'''''ANALYSIS OF STUDY:''''' Hank Wilson includes this reference in the various versions of his bibliography of references which he claims prove poppers to be hazardous.
:::This article attempted to determine whether nitrite use is an independent risk factor for HIV infection and if it interacts with unprotected receptive anal intercourse to further increase that risk.
:::They collected self-reports from homosexual male couples and performed a number of statistical tests to obtain odds ratios for associations between different behaviors and HIV infection.
:::The ratio of unprotected anal sex in participants who never used nitrites during sex (9.0) was higher than the number for those who sometimes used nitrites during sex (7.1), which refutes the theory that nitrite use leads to unsafe sex. Although the number for those who always used poppers during sex was higher (31.8), it is likely that a group that always uses any drug during sex may be a skewed population.
:::The odds ratio was similar when comparing the association of HIV seropositivity with use of several different recreational drugs (a range of 1.7 for cocaine use to 2.9 for nitrite use) or HIV seropositivity with nitrite use and unprotected anal sex. The similarity of these numbers implies that any type of drug use can be correlated to HIV seropositivity. The overall odds ratio for HIV infection in all study participants who used nitrites was only 1.6, which is very low.
:::An important control that was not included is the incidence of systemic bleeding during unprotected anal sex was not available. This could be the most important risk factor for HIV infection.
:::In their conclusion, they state that "It did appear that the relation between nitrite use and HIV infection was confounded, since the odds ratio decreased from 2.9 to 1.7 after we controlled for confounding variables as well the presence of a study partner. We suspect that the remaining increased risk associated with nitrite use results from residual confounding. We reanalyzed the data with nitrite use recoded into eight exposure categories using Rosner's model and found that nitrite use was no longer significantly associated with HIV infection."
:::Thus, controlling for confounding factors eliminates the associations between nitrite use and unprotected sex. This is a very important research result.
:::Finally, it is stated in the article that this group has never found an association between nitrite use and Kaposi's sarcoma. These results refute the proposed hypothesis that nitrites have an epidemiological role in KS.
*Penkower (1991) Behavioral, health and psychosocial factors and risk for HIV infection among active homosexual men: the multicenter AIDS cohort study. American Journal of Public Health, 81:194.
:::'''''ANALYSIS OF STUDY:''''' Hank Wilson includes this reference in the various versions of his bibliography of references which he claims prove poppers to be hazardous.
:::This report contains only one table and has the same flaw as the one that was previously discussed, which is that the number of seronegative (463) versus seropositive (181) participants is extremely disparate, making accurate conclusions difficult.
:::Regardless of this limitation, the data presented indicates that there is a similar increase in seroconversion for alcohol, cigarette, and recreational drug use, with heavy alcohol consumption being the most strongly associated with subsequent seroconversion. Although the researchers claim that nitrite use had the highest risk factor for seropositivity of all other drugs tested, they do not list the drugs that were studied or show the data for these drugs. They also state that drug users were more likely to engage in anonymous sex and had more partners, which are definitely confounding factors.
*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.
:::'''''ANALYSIS OF STUDY:''''' In an earlier paper, Soderberg obtained results after treating mice for five days, yet in these experiments mice were given 900 ppm isobutyl nitrite for 14 days. A similar study with a lower dose, up to 300 ppm for 18 weeks (J. Toxicol Environ. Health 15:823, 1985) reported no change in immune parameters.
:::In this study, the author found a reduction in mice body weight and spleen cells, in contrast to his previous work.
:::He also finds new parameters that nitrites effect. “The frequency of T-dependent plaque forming cells (PFC) was inhibited by 63% and the total number of PFC per spleen was reduced by 72% in nitrite-exposed mice.”
:::Once again, these results are meaningless because of the excessively high dose.
*Soderberg et al (1991) Inhaled isobutyl nitrite impairs T cell reactivity. Drugs of Abuse, Immunity, and Immunodeficiency, Ed. Freidman et al., Plenum Press, New York, pp. 265.
:::'''''ANALYSIS OF STUDY:''''' This is a short paper with only one figure, demonstrating the effects of isobutyl nitrite after treating mice for 45 minutes per day for 14 days.
:::After 24 hours, this treatment caused an impairment of T cell reactivity, but no effect on B cell function or hematopoeisis.
:::Other than Soderberg and his group's usual experimental design problems, they did not measure at any other time points to determine reversibility of nitrite effects.
:::Interestingly, other studies have shown that mice exposed to 300 ppm of nitrite for five days a week for 6.5 ours (over an 18 week period) had no changes in immune parameters (J. of Toxicology and Environmental Health, 15:828,1985 and J. of Toxicology and Environmental Health, 15:835, 1985).
:::Perhaps giving a smaller dose over a longer time period allows for recovery of the nitrite effects, or the drug is metabolized to non-harmful products.
*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.
*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."
:::'''''ANALYSIS OF STUDY'':''' In this study, the effects of volatile nitrite inhalation on the immune system of gay male volunteers was examined.
:::However, the amyl nitrite was administered in an unusual manner; namely, the apparatus used consisted of a 4 liter flask connected by tubing to a rubber inflatable breathing bag. Another tube connected the flask to room air, and a mouthpiece was attached to a side opening of the flask. Amyl nitrite pearls covered in gauze were broken and dropped in the bottom of the flask. Thirty seconds later, the subject exhaled, and then inhaled the air from the flask until the rubber bag collapsed and completed inspiration with room air (via the flask). The inspiration was held for 5 seconds before exhaling.
:::The drug dose was varied by altering the number of nitrite pearls dropped in the flask. This method of drug administration is very complicated and it does not represent the actual exposure that occurs when the drug is inhaled from a vial.
:::As everyone has a different lung capacity, it is impossible to standardize dose using this flask apparatus. Because of this dilemma, it is not understood why the nitrite was not inhaled directly from a vial to more accurately depict a physiological dose. Surprisingly, the authors claim that "the experimental protocol simulated the common episodic pattern of nitrite abuse." Since the drug was given three times a day (over a nine hour period) for either three or nine days using a complicated device, it does not follow that this protocol simulates nitrite abuse.
:::Another major flaw in this study is that there were only nine participants in each of the studies (short term or long term, consisting of three or nine day treatments, respectively, with drug administered three times a day) and the study was not repeated. This is a very low sample number and the experiments should have been repeated at least twice. Since the effects that were observed were readily reversible (see below) the same participants could have been used in an effort to replicate the data. Another approach could have been to recruit other volunteers for this study.
:::In these experiments, there were no changes in the number of T or B cells (which is considered to be an indicator of general immune function) in either the three or nine day experiments. The only statistically significant effect of nitrites observed was a 30% decrease in natural killer cell activity. This effect only occurred in the long-term study and returned to baseline within four days after cessation of drug exposure. This reversibility indicates that nitrite use may not have long term effects. Other immune function tests were not performed and nitrite exposure had no effect on cell proliferation. These results are not compelling evidence for a major effect of nitrite inhalation on the immune system.
*Martin, (1990) Drug use and unprotected anal intercourse among gay men. Health Psychology, 9(4):450.
:::'''''ANALYSIS OF STUDY:''''' Results are reported from a longitudinal study of 604 NYC gay men spanning four 12-month periods from 1980 to 1987 indicating that as the acquired AIDS epidemic progressed, the link between drug use and high risk-sex diminished.
:::Furthermore, initiation of drug use with sex is not associated with subsequent increases in lower rates of unprotected anal intercourse.
:::In this report, participants were asked how many times they used drugs in conjunction with unsafe sex over the past year. This type of question is obviously subject to recall bias. Another problem with this study is that respondents who used one type of drug were likely to use other drugs as well, which confounds the issue of nitrite use being directly related to unsafe sex.
:::The author found that there was a correlation between men using drugs (including nitrites) with unsafe sex and that both behaviors decline over a seven year period. These behaviors declined to the point that none of the associations between any specific drug use and unprotected receptive anal intercourse were statistically significant, which Wilson fails to mention when using this study to make his point.
:::Interestingly, within this article, the author reported contradictory results. They found that there is no consistent pattern associating initiation of drug use with sex and high-risk intercourse, either receptive or insertive. This type of data further refutes the hypothesis that nitrite use influences risky behavior.
:::Finally, the authors stated that "We have evidence that favors (but that by no means confirms) a causal interpretation of the link between drug use and high-risk sex among gay men."
:::They also said: "On the other hand,...noncausal interpretations of the link between drug use and risk taking may be more parsimonious."
:::In the discussion section of the paper, they say that "conclusions based on an epidemiologic field study of the kind we have conducted are subject to threats to validity, particularly to drawing causal inferences."
:::These kinds of statements do not support Wilson's hypothesis.
*Burcham et al. (1989) Incidence and risk factors for human immunodeficiency virus seroconversion in a cohort of Sydney homosexual men. The Medical Journal of Australia, 150:634.
:::'''''ANALYSIS OF STUDY:''''' Hank Wilson includes this reference in the various versions of his bibliography of references which he claims prove poppers to be hazardous.
:::In this study, the researchers state that the relative risk of seroconversion was significantly higher among subjects who abused nitrite inhalant during the seroconversion period and that there was a significant relationship between nitrite use and anal receptive intercourse.
:::From these two correlation's, a causal relationship cannot be demonstrated between nitrite use and seroconversion. Furthermore, the author himself claimed that the drug use may have been a correlate of high-risk behavior and, which is the only conclusion that can be accurately formed.
*Dax et al. (1988) Effects, of nitrites on the immune system of humans. Health Hazards of Nitrite Inhalants. National Institute of Drug Abuse Research Monograph Series. #83, 75.
:::'''''ANALYSIS OF STUDY:''''' In this study using eight HIV- male volunteers, the investigators found that amyl nitrite inhalation caused an initial suppression in immune function that was followed by an overshoot seven days after cessation of drug. This study had a low sample number and was not repeated.
:::These results are also contradictory to results obtained by other research groups.
:::If the work presented in this paper is accurate, one could interpret the overshoot in immune activity as evidence for nitrite use causing an increase in immune function.
:::This conclusion refutes Hank Wilson's oft-repeated proposal that nitrites are significantly harmful to the immune system.
*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.
:::'''''ANALYSIS OF STUDY:''''' In this study, five of six different alkyl nitrites, including isobutyl nitrite, tested positive for mutagenicity. Since it is not known what the actual dose of nitrite is after inhalation, it is difficult to know if the concentration used in these mutagenecity studies is anywhere near the physiological dose of nitrite.
:::Furthermore, these types of studies do not account for metabolism of the drug, which occurs in the intact animal.
* 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
* Harry W. Haverkos, M.D., John A. Dougherty, Ph.D. (1988). ''[http://www.drugabuse.gov/pdf/monographs/83.pdf Health Hazards of Nitrite Inhalants]'', NIDA Research Monograph 83
* Reinisch , June, Ph.D., [http://www.virusmythpoppersmyth.org/kinsey_institute/]Kinsey Institute: Poppers and AIDS, April 1, 1988;
*Lycka (1987) Amyl and Butyl nitrites and telangiectasia in homosexual men. Annals of Internal Medicine, 106: 476.
:::'''''ANALYSIS OF STUDY:''''' This article is actually a letter to the editor that suggests that nitrites may cause telangiectasia (vascular dilations seen in many diseases) on the chests of homosexual men. Lycka claims that since nitrites are vasodilators, and that they may induce this condition.
:::Hank Wilson includes this reference in the various versions of the bibliography he sends to people. However, this is not a scientific article and does not belong in a reference list.
*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.
:::'''''ANALYSIS OF STUDY:''''' Khaled tested the effects of isobutyl nitrite on coenzymes of B12 and folic acid, which are important in growth and proliferation of mammalian cells.
:::The rationale for the experiment is that nitric oxide, a breakdown product of isobutyl nitrite, can oxidize and inactivate these cofactors. Therefore, they measured the effects of isobutyl nitrite on the structures of the coenzymes using nuclear mass resonance spectroscopy.
:::Interestingly, they see no effects when isobutyl nitrite is solublized in alcohol, and changes in structure when isobutyl nitrite is added to these compounds in water, in which isobutyl nitrite is virtually insoluble.
:::They do not address this discrepancy.
:::Furthermore, these studies do not replicate an in vivo situation, in which inhaled isobutyl nitrite may not encounter these cofactors, especially in concentrations high enough to be effective.
* 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
* 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.
:::'''''ANALYSIS OF STUDY:''''' These researchers claimed that isobutyl nitrite causes a decrease in natural killer cell activity in mice when injected intraperitoneally or inhaled. They injected 0.25 mls of isobutyl nitrite twice before assay, which is not a physiological administration of this compound.
:::In addition, this is the amount that a human would 'inhale', not inject directly into the body.
:::The metabolism of the nitrite could be very different when given as an intraperitoneal injection rather than the usual inhalation route.
:::For inhalation experiments, mice were placed twice a day for two-three minute (for seven days) in a beaker containing a petri dish with two ml of isobutyl nitrite. They did not attempt to calculate the dose that was given by this exposure, although again, this amount more closely approximates a human dose. Lotzova's group claims to use the maximal dose tolerated by the mice, which implies that these doses were near lethal.
:::Another flaw in the design of these experiments is that they were not replicated. It is not understood why such a standard scientific procedure was not utilized, unless a replication of the studies did not confirm the initial results.
:::Finally, these investigators obtained results that contradict work by Soderberg. Lotzova found a decrease in tumor-binding capacity of natural killer cells, whereas Soderberg found no change in this parameter. Considering this discrepancy, and more importantly, the dosing regimen utilized, these studies do not establish a role for nitrites in a decrease in tumoricidal activity.
* 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
:::'''''ANALYSIS OF STUDY:''''' In these studies, isobutyl nitrite in solution incubated with human white blood cells had a nonspecific cytotoxic effect. They state that a 1% solution was highly toxic to the leukocytes.
:::There was no rationale for the dosing regimen, and considering that nitrites decompose rapidly, it is highly unlikely that this concentration of drug reaches blood cells.
:::Hersh claims that the effects of isobutyl are not reversible by washing it out of the cultures, which is not in agreement with the in vivo studies referenced by Hank Wilson that demonstrate reversibility of nitrite effect.
:::In addition, in Hersh's work, nitrite had cytotoxic effects on other cell types, including a breast cancer cell line, which indicates that the nitrite is not selective for immune cells. These provide further evidence that the doses used in the experiments are too large.
:::Another criticism of this work is that it is performed in vitro, which is not a physiological situation. This is a non-physiological situation.
* Jorgensen K.A., Lawesson S.O. (1982), Amyl nitrite and Kaposi's sarcoma in homosexual men. N. Engl. J. Med. 307, 893
*Watson (1982) The use of amyl nitrite may be linked to current epidemic of immunodeficiency syndrome. Unpublished paper submitted to the Journal of the American Medical Association and the Advocate (the largest national gay magazine).
:::'''''ANALYSIS OF STUDY:''''' Hank Wilson includes this reference in the various versions of the bibliography he sends to people. Citing a paper that was submitted, but not published, is an example of his apparent inability to provide substantiated evidence supporting his claims.
:::Papers that are rejected from scientific journals (and non-scientific publications) are not valid research. Such articles are not worthy of inclusion in a document attempting to establish a claim. Furthermore, such references erode the credibility of the author.
* I. Quinto, "The Mutagenicity of Alkylnitrites in the Salmonella Test" (translation from the Italian), Bolletino Societa Italiana Biologia Sperimentale, 56:816-820, 1980.
* Lisa Ringold, PhD pharmacology: A Critical Review Hank Wilson's Bibliography/References list regarding Anti-Popper Research [http://www.virusmythpoppersmyth.org/hank_wilson_references/]
*Voeller, Bruce, Ph.D., "Are Poppers Safe?" , [http://www.virusmythpoppersmyth.org/mariposa_occasional_paper/ May 1986]
*Varnell, Paul, Chicago Free Press (and other gay newspapers), Gay/HIV/AIDS activist: [http://www.virusmythpoppersmyth.org/paul_varnell/] - "The controversy over poppers"
*Burton, Stephen, M.D., [http://www.virusmythpoppersmyth.org/pink_paper_london/]"Poppers in Perspective", Pink Paper April 8, 1989, London, UK
*Wicker, Randy, 1999 on [http://www.virusmythpoppersmyth.org/poppers_return_no_evidenc/]'poppers=death'
*Bauman, Robert, Member U.S. House of Congress(Retired); [http://www.virusmythpoppersmyth.org/robert_bauman/]History of Congressional Investigation on 'Poppers'
*Kennedy, Edward, U.S. Senate, Chairman: Senate Committee on Labor and Human Resources [http://www.virusmythpoppersmyth.org/us_senate_alkyl_nitrite_s/](May 4, 1988) "Alkyl Nitrite Study"
*Bowman, Ted; "The Poppers Story [http://www.virusmythpoppersmyth.org/poppers_story/]-- the History of Nitrite Odorants"
*Prusiner, Stanley, Institute for Neurodegenerative Diseases, Department of Neurology and Department of Biochemistry and Biophysics, University of California, San Francisco, "Discovering the Cause of AIDS"[http://www.virusmythpoppersmyth.org/cause_of_aids/], The American Association for the Advancement of Science
*Curran, James, M.D., Novitch, Mark, M.D., and others [http://www.virusmythpoppersmyth.org/guide_to_alkyl_nitrites_s/]'A Guide to Alkyl Nitrites and Poppers'
*DuPont, Robert L, Clinical Professor of Psychiatry, Georgetown University School of Medicine Washington, D.C.; former Director of the National Institute on Drug Abuse NIDA 1973-1978; [http://www.virusmythpoppersmyth.org/gateway_drugs/] Nitrites and Gateway Drugs (July 1990)
*O'Brien, Stephen J., Ph.D., Director, Laboratory of Genomic Diversity, National Cancer Institute, NIH; The HIV-AIDS Debate Is Over: What to tell your patients when they ask if HIV causes AIDS[http://www.virusmythpoppersmyth.org/s_j_obrien_hivaids_debate/], NEWSLINE, Volume 3, Issue 1 • February 1997
* [[John Lauritsen|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: [http://www.rethinkaids.com/body.cfm?id=58].
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