NIDA Meeting Calls For Research
Into The Poppers-Kaposi's Sarcoma Connection *

Copyright 1994 by John Lauritsen



Gaithersburg, Maryland, 24 May 1994.

    The National Institute on Drug Abuse (NIDA) sponsored a high-level meeting, “Technical Review: Nitrite Inhalants”, held outside Washington, DC on the 23rd and 24th of May, 1994. The toxicologists, AIDS researchers, and others present reached a consensus urging research into the connection between the nitrite inhalants (or “poppers”) and Kaposi's sarcoma (KS). The meeting was organized by Harry Haverkos of NIDA, who has been writing since 1985 about the health hazards of the nitrite inhalants.[1]
    Robert Gallo, as unofficial voice of the AIDS Establishment, disclosed important revisions in the AIDS-paradigm. It is now necessary to consider co-factors. No longer is HIV believed to cause KS by itself; at most it may aggravate KS after it has been caused by something else. No longer is HIV believed to kill T-cells; whatever damage it allegedly does, it does indirectly. Speaking informally, Gallo discussed the latest thinking on the nature and causes of KS.
    The meeting had implications that went beyond the issue of the nitrites, important as that may be. It indicated a willingness, on the part of the Public Health Service, to re-think the basic premises of the AIDS model that has prevailed since 1984. It is high time, for the HIV-AIDS hypothesis has been a total failure, both in terms of public health benefits and in terms of making accurate predictions.
    Molecular biologist Peter Duesberg, the foremost critic of the HIV-AIDS hypothesis, attended the meeting as an invited observer. He has designed experiments, and is waiting for funding, to examine the effects of long-term nitrites exposure in animals. From attacks on Duesberg in the popular and quasi-scientific press, one might have expected him to be treated as a pariah. This was not at all the case: the other scientists were friendly, and listened to him with respect when he discussed points of retrovirology, on which he is one of the world's leading experts. A reconciliation took place between Robert Gallo and Peter Duesberg; the two are on friendly terms again, for the first time since 1987, when the first interview with Duesberg appeared in the New York Native.[2]
    For the rest of this article, I'll give some background information on poppers, followed by a chronological account of the NIDA meeting and my own conclusions.

Background: Poppers and their toxicities
    As a prescription drug, amyl nitrite was used by elderly people for emergency relief of attacks of angina pectoris (heart pain).
    Historically, the use of the nitrite inhalants (amyl nitrite, butyl nitrite, isobutyl nitrite, etc.) for recreational purposes has been limited almost entirely to gay men. The first reports of recreational use date from the early 1960s, after the amyl nitrite prescription requirement was eliminated by the FDA. The drug appeared to intensify and prolong the sensation of orgasm. It facilitated anal intercourse, by relaxing the smooth sphincter muscles and deadening the sense of pain.[3]
    The FDA re-instated the prescription requirement in 1969. In 1970 a new industry stepped into the breach, marketing little bottles containing mixtures of butyl and isobutyl nitrite. By 1974 the poppers craze was in full swing. Ads for them appeared in all gay publications. At gay discotheques men could be seen, shuffling around in a daze, holding poppers bottles under their nose. The miasma of nitrite fumes was taken for granted at gay gathering places: bars, baths, leather clubs. Some gay men were never without their little bottle, from which they snorted fumes around the clock. Two separate studies in the 70s found that some gay men could no longer perform sexually without the use of poppers.[4]
    The toxicities of the volatile nitrites were well known before the advent of AIDS. In 1980 Thomas Haley, one of America's leading toxicologists, published a two-page summary of nitrite toxicities, with 115 references listed. Here are a few of the highlights:


    Also in 1980 appeared the first of several studies to demonstrate that the volatile nitrites are powerfully mutagenic.[6]  (That is, they cause cells to mutate, they cause damage to the chromosomes.)  This is cause for concern, as almost all known carcinogens are also mutagens.
    Subsequent studies, both in vitro and in vivo, have shown that poppers damage the immune system. They cause two kinds of anemia: Heinz body hemolytic anemia and methemoglobinemia. They damage the lungs. They have the potential to cause cancer by producing deadly N-nitroso compounds in interaction with many common drugs and chemicals, including antihistamines, artificial sweeteners, and pain killers.[7]
    When the first cases of AIDS were identified in 1981, or the predecessor cases of GRID (Gay Related Immune Deficiency), poppers were high on the list of etiological suspects. Here was a drug used heavily and almost exclusively by the group of people getting sick. Nevertheless, despite compelling epidemiological and toxicological evidence, the Centers for Disease Control (CDC) hastened to exonerate poppers. They did so for two reasons, both of which were spurious. First, the CDC found AIDS patients who had never used poppers; therefore, argued the CDC, poppers could not be the cause. The CDC's faulty assumption was that “AIDS” constituted a single, coherent disease entity with a single cause. Second, the CDC conducted a brief mice study in 1982-1983, and claimed to find “no evidence of immunotoxicity”. These results are contradicted by several other studies, which did find that the inhalation of nitrite fumes causes immune suppression in mice. The reasons for the negative findings of the CDC mice study were explained at the Gaithersburg meeting by one of the investigators, Daniel Lewis, about which more below.

The Epidemiology of Nitrite Use
    After a welcome by Richard A. Millstein, Deputy Director of NIDA, Harry Haverkos opened the meeting on Monday, May 23 with a brief overview of the volatile nitrites, their use and regulation. He then turned the session over to Zili Sloboda of NIDA, who moderated the morning session devoted to epidemiology. She stressed the “importance of prevention messages”.
    Andrea Kopstein of NIDA discussed the ambiguities involved in such phrases as “inhalant abuse”. The inhalants are diverse substances that happen to be defined by the route of intake. The lack of clarity as to what constitutes an “inhalant” causes confusion in responses to questions in surveys. She presented studies of lifetime use of nitrites among sex and ethnic groups, which showed that use of amyl and butyl nitrite among U.S. males decreased after 1986, though inhalant use remained just as high.
    Lisa Jacobson, of the Johns Hopkins School of Hygiene and Public Health, presented data from the much used and abused MACS study, a cohort of gay male volunteers. Those men who were “sero-prevalent” (that is, HIV-antibody-positive on entry into the study) had much higher poppers use. Among all groups in the study, the use of poppers declined.
    Kenneth Mayer, a physician living in the Boston area, was among the first to sound the warning about poppers to gay men.[8]  He discussed surveys, which found that the use of poppers is a risk factor for becoming HIV-antibody-positive. But what does that mean?  He mentioned two possibilities: being HIV-antibody-positive might be a marker for other health risks, or it might be a marker for illness. He posed the basic question: which is more hazardous, unsafe sex or drug use?
    The highlight of the morning session was “Advertising Trends”, presented by Hank Wilson, a San Francisco activist who in 1981 founded the Committee to Monitor Poppers.[9]  He began by saying that, with regard to poppers, gay men had been uninformed, misinformed, partially informed, and confused. He then showed stunning color slides of several dozen poppers ads, from the early 70s through the late 80s. This must rank among the most brilliant advertising campaigns in history. Within only a few years hundreds of thousands of men were persuaded that poppers were an integral part of their own “gay identity”. The ads conveyed the message that nothing could be butcher or sexier than to inhale noxious chemical fumes. Bulging muscles were linked to a drug that is indisputably hazardous to the health.
    Beginning in the early 70s ads for poppers appeared in all of the gay press — ads for special inhalers — an ad for a brand named “Discorama”, specifically targeted at disco dancers. One ad gave an 800 number, with the message, “We'll pay you to try...” (the free trial tactic that has also been used on the street by dealers of heroin, crack, and other such commodities). An ad for the poppers brand RUSH focussed on the phrase, “Better Living Through Chemistry” — and no irony was intended.
    However, warnings about the dangers of poppers began to appear in both the gay and the mainstream press, and for the decade of the 80s, these messages competed with disinformation from the poppers industry and their allies. Wilson showed the front page of a December 1981 issue of the New York Native, with a banner headline, “Do poppers cause cancer?”. This message got across even to people who just glanced at it on the newsstand. A Pittsburgh paper. OUT, repeated the same heading. The City of San Francisco required than a warning notice be placed at all points of sale for poppers. The June 4-17 1984 issue of the New York Native carried an article, “Poppers: The Writing On The Wall”. On 19 July 1985 the Seattle Gay News published a boxed warning on poppers. And in 1985 poppers were banned from the most popular disco in San Francisco. The mainstream press in San Francisco also began to carry the message that poppers were dangerous.
    But the poppers industry had its own resources. A 1983 pamphlet published by the CDC, “What gay and bisexual men should know about AIDS”, claimed that there was no relationship between AIDS and poppers, on the basis of a single mice study (to be discussed below). In effect, the government gave the green light on poppers use. The CDC's mice study was cited in a press release sent out by Joseph F. Miller, President of Great Lakes Products, the world's largest manufacturer of poppers. Miller's press release, run by most of the gay press, claimed that “Jim” Curran of CDC's AIDS Branch had given him a guided tour of the CDC and assured him there was no relationship between poppers and AIDS. When Curran responded with a letter saying that he had been misinterpreted, and that poppers may play a role as cofactor in some of the illnesses in the syndrome, his letter was ignored by the gay papers who had run the press release from Miller. Great Lakes Products followed through with a series of ads in the Advocate, entitled “Blueprint For Health”, which gave the impression that poppers, like vitamins, fresh air, exercise and sunshine, were an ingredient in the healthy lifestyle.
    In 1987 a San Diego gay paper began running full-page ads for poppers. The Windy City Times in Chicago ran full-page ads, as well as articles attacking the critics of poppers. Heartland, a mid-west gay paper owned by Great Lakes Products, ran ads and articles defending their product. The San Francisco Sentinel ran an ad that warned of an impending ban on poppers ban, and urged its readers to “STOCK UP!”. In 1992, three years after poppers had been outlawed by act of Congress, a stand at a gay street fair in Chicago offered iced tea for $1 and poppers for $5. In 1992 the manufacturer of RUSH sent out a mail order ad to “preferred customers”.
    Hank Wilson concluded his presentation by making the point: Poppers are easy and cheap to make, they are highly profitable, and there is a demand for them. Therefore, they will always be available. For this reason, education is essential.

Do Nitrites Lead to Increased Risky Sexual Behavior and HIV Transmission?
    The afternoon session of 23 May began by considering the relationship between use of poppers and becoming HIV-antibody-positive. Whether this matters depends on whether or not HIV is the cause of “AIDS”. Since I don't believe that HIV is even pathogenic, and consider the survey research (a.k.a. “epidemiology”) performed by academics, physicians, and members of the Public Health Service to be far below professional standards, I took a rather dim view of this session.
    In broad strokes — the speakers indicated that those who were HIV-antibody-positive were more likely to have more sex and to use all drugs more heavily.
    Ken Mayer presented Boston data indicating a very high Odds Risk (OR) of seroconversion for those who always used poppers when they had passive anal intercourse. He pointed out that this was biologically plausible, inasmuch as poppers relaxed the smooth sphincter muscle, dilated the blood vessels, and deadened the sense of pain (thus increasing the risk of anal trauma).
    In the discussion period I put two questions to Mayer: 1) “What is the basis for determining ‘HIV infection’?  The antibody tests?”, and 2) “Is there really evidence that these people had a viral infection, and if so, was the virus sufficiently biochemically active as to cause illness?” He replied that the ELISA and the Western Blot antibody tests were used, and that they were sometimes followed up by viral culture. This question is important, as an article in Bio/Technology last year demonstrated that the antibody tests are unvalidated and extremely unreliable — that many HIV-antibody-positive people have never been infected by the virus itself, which in any event is virtually never biochemically active to a degree that would enable it to cause illness.[10]
    Jay Philip Paul, an AIDS prevention specialist in San Francisco, 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.

Do Nitrites Suppress the Immune System?
    The second afternoon session on 23 May dealt with in vivo toxicological studies, two involving mice and one involving human subjects.
    First was Daniel Lewis of the National Institute for Occupational Safety and Health. He was one of those who conducted the 1982-93 CDC mice study that was the basis of the MMWR news item (9 September 1983), which claimed to find “no evidence of immunotoxic reactions”. In that study the doses were extremely low, approximating levels to be encountered as background exposure (used as “room odorizer”, workers in a poppers factory) rather than those encountered when using poppers as a drug (i.e., inhaling directly from the bottle).
    Lewis explained that, in determining the dose, they had to adjust it below the level where they were “losing” the mice — however, the supplier of the mice later disclosed that the mice were suffering from a low-grade infection. This means that the deaths of the exposed mice may well have been due to immunotoxicity — exactly what the study conclusions claimed not to find — rather than the acute toxicity of the nitrite fumes. The end result was that the dose was far too low to be meaningful.
    The study was not blinded, as the mice inhaling IBN vapors developed a “yellowish tinge”. Although there were no significant changes in body weight, there were reduced liver and thymus weights, and an increase in spleen weights. 100% of the exposed mice developed methemoglobinemia. The white cell count went down sharply.
    In the question period I stated that other mice studies had found that nitrite inhalation caused immune suppression in mice. How did Lewis explain the discrepancy between his findings and the others?  His answer was short and sweet: “Dosage and length of exposure”.
    The second mice study was presented by Lee Soderberg, of the University of Arkansas. His mice inhaled 900 ppm nitrite fumes for 45 minutes daily for 14 days, then were allowed to rest for 1-3 days. Then tests were performed. They found that there were decreases in both body and spleen weight, the cells in the spleen and in the blood were reduced, the response to conA was reduced (-28%), the T-dependent cells were very sharply reduced, accessory cell function was affected (there was reduced ability to support proliferation of normal T-cells), the macrophage functions were greatly reduced (especially tumoricidal activity). The recovery of immune functions generally took about a week; however it took longer for macrophage cytotoxicity to recover (about 2 weeks).
    Soderberg and his colleagues reached the conclusion that exposure of mice to nitrites via inhalation impaired:
        • T-dependent antibody responses
        • T-mediated cytotoxicity
        • macrophage tumoricidal activity

    In the question period Peter Duesberg raised the issue of reversibility: What about something that goes on for years?  Analogies here would be the length of exposure required to achieve a causal relationship between cigarettes and lung cancer, or between alcohol and cirrhosis. Soderberg replied that his team had “no data on more chronic exposure”.
    The third speaker was William Adler of the National Institutes of Health. His study was of 8 human volunteers, HIV-antibody-negative males, who inhaled poppers three times per day for one week, and then intermittently for another week and a half. Baseline immunological test batteries were run before, during, and after exposure. The investigators found that the main change was in natural killer (NK) cell activity, which dropped very sharply. They reached the conclusion: “The results showed that exposure to amyl nitrite can induce changes in immune function even after short exposure to moderate doses.”

Do Nitrites Act as a Cofactor in Kaposi's Sarcoma?
    The second day of the meeting, 24 May 1994, addressed the key question: Do poppers play a role in causing KS?  The first speaker was Harry Haverkos, who began by showing a slide indicating that there appear to be four kinds of KS:

    1. Classic KS, occurring among older men, indolent.
    2. African KS: 25-40 age group, first indolent then fatal in 5-8 years.
    3. Iatrogenic KS (e.g., renal transplant): indolent or fulminant.
    4. Epidemic or AIDS KS: gay white males, fulminant, survival 1-3 years.

And he posed the question: “Are these all the same?”
    Haverkos cited the cases of HIV-negative cases of gay men with KS (16 in the practice of one physician alone). He reviewed the epidemiological data, which were inconsistent. Four studies found a strong and dose-related relationship between the use of nitrites and the development of KS — however, other studies did not.
    He cited a recent study which found that the volatile nitrites are even more powerfully mutagenic than had previously been thought. Iso-butyl nitrite vapors were 11 times as mutagenic as iso-butyl nitrite in solution.[11]
    Haverkos presented a slide: REASONS TO CONSIDER NITRITE INHALANTS A COFACTOR IN THE PATHOGENESIS OF KAPOSI'S SARCOMA (KS) IN AIDS:


    He followed this with another slide: WHY AIDS-RELATED KAPOSI'S SARCOMA (KS) IS NOT EXPLAINED BY A SEXUALLY TRANSMITTED AGENT:


    In conclusion Haverkos presented a series of recommendations:


    The next speaker was Harold Jaffe of the CDC, who said that he would take a “con position” for the purpose of the meeting, even though he was open to the possibility that the nitrites might play some role in causing or aggravating KS. He argued that the KS co-factor is likely to be a transmissible agent, since one study had found an association between KS and rimming. The risk for KS is highest among those who lead a particular kind of sexual lifestyle, characterized not only by nitrites use, but also by multiple, anonymous sexual partners.
    In the question period I made the point that the nitrites obviously could not be the sole cause of one or all of the forms of KS. The question is whether they play a causal role in some or most of the cases of epidemic (AIDS) KS. Their biochemical properties are consistent with such a role. In contrast, nothing can be said about a microbe which has yet to be discovered.
    Following Jaffe's presentation, Haroutune Armenian of the Johns Hopkins School of Hygiene and Public Health presented a re-analysis of data from the MACS study. He found a stronger association between rimming and KS than between poppers and KS. The use of marijuana and hashish were found to be high risk factors for KS. Not only did he not find a dose-related between poppers use and KS, he they found exactly the opposite: a strong, statistically significant negative correlation. In other words, the more poppers you use, the less likely you are to develop KS. Obviously this violates common sense and contradicts other studies, which found a strong positive correlation. The most likely explanation is that Armenian's data are wrong. It should be noted that Armenian merely re-analyzed data that had been collected by others, in a study designed by others.

Robert Gallo Revises the Paradigm
    The final speaker on the question of whether poppers play a role in causing KS was Robert Gallo of the National Cancer Institute, who is still regarded by many as America's foremost AIDS expert. He began by saying that he wanted to open up basic questions, and had no fixed opinion regarding co-factors for KS — whether chemical, viral, or a combination. Though not in agreement with all that Harry Haverkos had said, for example the donor recipient or localization arguments, he was willing to be persuaded.
    To my knowledge, this was the first time for Gallo or any other top “AIDS expert” to admit publicly that HIV was not the primary cause of KS. He said: “We believe that HIV in KS is an enormous catalytic factor, but there must be something else involved.”  He continued:


Gallo then went on to revise the most basic premise of the AIDS construct: the assumption that an underlying condition of “immune deficiency” is responsible for causing, indirectly, the various AIDS-indicator diseases. He said:


    And he posed a few additional questions:


    Gallo then proceeded to present a summary of findings from his laboratory regarding KS:


    During the question period Harry Haverkos responded to Gallo's earlier criticisms. When looking at national data, we do see a decline of KS among US gay men. On the localization phenomenon: the product, nitrites, is in the lungs and the blood vessels; it is where the lesions occur, whereas HIV is not there. We do not see the expected donor-recipient connection — there is not a single reported case of KS among blood recipients where the donor had KS.
    Gallo then admitted: “The nitrites could be the primary factor. What if the nitrites had the ability, interacting with endothelial cells, to produce to produce a tremendous amount of 'X', of inflammatory cytokines?”
    Peter Duesberg raised the point that HIV couldn't always play a role in KS, to which Gallo replied:


    Someone then asked, “What are the inflammatory cytokines?”  Gallo replied: “The inflammatory cytokines are IL1 [interleukin 1], TNF [tumor necrosis factor], and gamma interferon. In gay men, the inflammatory cytokines are increased before HIV infection.”
    In response to a question about AIDS-related dementia he replied: “The mechanism of dementia in HIV-infected people is totally unknown.”
    Glen Hopkins, an activist from Los Angeles, raised the question of high dose, long-term exposure. Poppers, after all, do promote mutagenesis. To this Gallo replied: “That's the most important thing, mutagenesis. Also perhaps nitric oxide.”

General Discussion
    The final, general discussion, was moderated by Paul Stolley of the University of Maryland School of Medicine. Robert Gallo started to leave, got to the door, hesitated, then came back and sat next to Peter Duesberg. Within a few minutes he had his arm around him, and stayed there for the duration of the final session.
    When discussion focussed on what research ought to be done, Gallo spoke strongly in favor of an animal model, and said that Duesberg's research ought to be funded.
    There was general agreement that the toxicology and epidemiology of nitrites use ought to be rigorously investigated.
    My own conclusions, which I expressed inadequately at the meeting, are as follows:


Conclusion
    In light of the statements made by Gallo, it is hard not to think of the tens of thousands of gay men with KS who have died, and of the treatments they received. If HIV is not the cause of KS, then how appropriate were the nucleoside analogue drugs, like AZT and ddI, whose theoretical basis is the HIV-AIDS hypothesis?  Similarly, if KS is really not a malignancy, how appropriate were chemotherapy drugs based on the assumption that KS is a malignancy?  Did these men die from KS, or from the treatments they were given? 
    It may be hoped that this meeting is a signal of greater willingness on the part of the AIDS Establishment to re-consider the basic AIDS paradigm. Kaposi's sarcoma as an AIDS phenomenon remains a puzzle, and no hypothesis so far put forward seems fully adequate to explain it. It could be that KS comprises diverse conditions with diverse causes. Having said that, however, the nitrites-KS hypothesis is very much alive, more than a decade after its precipitous rejection by the CDC.

References

1. 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.

2. John Lauritsen, “Saying No To HIV: An Interview With Prof. Peter Duesberg, Who Says, ‘I Would Not Worry About Being Antibody Positive’”, New York Native, Issue 220, 6 July 1987.

3. For an excellent overview of poppers and their toxicities, read “Nitrite Inhalants: Historical Perspective”, by Guy R. Newell et al., in NIDA Monograph 83 (cited above).
    See also Chapter X: “Poppers: The End of an Era” in John Lauritsen, The AIDS War, New York 1993.

4. Ronald W. Wood, “The Acute Toxicity of Nitrite Inhalants”, in NIDA Research Monograph 83 (cited above).

5. Thomas H. Haley, “Review of the Physiological Effects of Amyl, Butyl, and Isobutyl Nitrites”, Clinical Toxicology, pp. 317-329, 1980.

6. I. Quinto, “The Mutagenicity of Alkylnitrites in the Salmonella Test” (translation from the Italian), Bolletino Societa Italiana Biologia Sperimentale, 56:816-820, 1980.

7. These points are covered in various chapters in NIDA Research Monograph 83 (cited above).

8. Kenneth Mayer and James D'Eramo, “Poppers: A Storm Warning”, Christopher Street, Issue 78.

9. I have collaborated with Hank Wilson since 1983. In 1986 we published a little book, Death Rush: Poppers & AIDS, which included an annotated bibliography. It is now online: to read it click here.

10. Eleni Papadopulos-Eleopulos et al., “Is a Western Blot Proof of HIV Infection?”, BioTechnology, June 1993, pp. 691-707.

11. 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.


* This article was published in the New York Native, issue 582, 13 June 1994, and has been posted in various newsgroups on the Internet. It may be shared electronically or in the form of hard copy, but it may not be reproduced for profit without permission from the author.


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